1. Hypervalent Iodine Reagents in Organic Synthesis Andrew T. Parsons March 23, 2007

2. Outline Background Iodine(III) reagents Iodine(V) reagents Conclusions

3. Hypervalent Iodine: An Introduction Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523-2584. Hypervalent iodine: Species that exceed eight electrons in the valence shell, typically I III and I V –Can accommodate up to 12 valence electrons: –Species with 10 valence electrons are more common:

4. 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 λ 3 -iodanes Iodine(V) compounds are referred to as λ 5 -iodanes, periodanes, or periodinanes Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.

5. Structural Characteristics λ 3 -iodanes: λ 5 -iodanes: Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.

6. Outline Background Iodine(III) reagents Iodine(V) reagents Conclusions

7. Preparation of I III Reagents Most reagents are prepared directly from iodobenzene: Varvoglis, A. Tetrahedron 1997, 53, 1179-1255.

8. Reactions of Iodine(III) Compounds Reactivity is driven by the electrophilic nature of I III –Typical reactions proceed through an initial nucleophilic attack of the iodine center: –PhIX is an excellent leaving group, on the order of 10 6 better than – OTf, and therefore substitutions and reductive eliminations are prevalent

9. Reactions of Iodine(III) Compounds: Oxygenations

10. 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 I III 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.

11. Oxidations with Iodosylbenzene Useful in the α-hydroxylation of ketones α-Hydroxylation of ketones can be carried out using CrO 3, typically with higher yields PhIO is a non-toxic alternative to Cr VI 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.

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

13. Mechanism of α-Hydroxylation Moriarty, R. M. J. Org. Chem. 2005, 70, 2893-2903.

14. 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

15. Catalytic α-Acetoxylation of Ketones Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244-12245.

16. Catalytic Cycle Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244-12245.

17. 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.

18. Oxidative Rearrangements of Aryl Alkenes Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159-6163.

19. Oxidative Rearrangements of Aryl Alkenes Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159-6163.

20. 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.

21. Oxidative Cleavage of Alkenes Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772-2773.

22. 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.

23. Oxidative Cleavage of Alkenes Suggests that an epoxidation precedes cleavage Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772-2773.

24. Reactions of Iodine(III) Compounds: Oxidation of Phenols Previously: Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.

25. Application to Spirocyclizations Tether a nucleophile to the phenol: Possible applications in natural product synthesis

26. Spirocyclization of Phenols: Early Studies Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987, 52, 3927-3930.

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

28. Current Standard: Catalytic Spirocyclizations Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6192-6196.

29. Catalytic Cycle Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6192-6196.

30. Applications in Total Synthesis Synthesis of Aranorosin: Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195-7203.

31. PhI(OCOCF 3 ) 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.

32. PhI(OCOCF 3 ) 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.

33. 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.

34. Applications in Total Synthesis Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H. Angew. Chem. Int. Ed. 2005, 44, 5857-5860. Synthesis of (+)-Tanikolide

35. Carbon-Carbon Bond Forming Reactions

36. 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.

37. 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.

38. Applications in Total Synthesis Synthesis of (±)-Stepharine Honda, T.; Shigehisa, H. Org. Lett. 2006, 8, 657-659.

39. 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.

40. 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.

41. 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.

42. Outline Background Iodine(III) reagents Iodine(V) reagents Conclusions

43. Preparation of I V Reagents 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. Caution: There have been reports of violent explosions occurring upon heating of these reagents to >200 °C

44. 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.

45. 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.

46. 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.

47. 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.

48. Applications in Total Synthesis Efforts toward the synthesis of Phomoidride B Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755-767.

49. 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.

50. 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.

51. 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.

52. 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.

53. 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.

54. Oxidation of Carboxamides to Nitriles Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662-665.

55. Oxidation of Carboxamides to Nitriles Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662-665.

56. Proposed Mechanism Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662-665.

57. 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

58. Acknowledgements Cory Bauch Ashley Berman Mary Robert Nahm Justin Potnick Rebecca Duenes Matthew Campbell Shanina Sanders Andy Satterfield Steve Greszler Chris Tarr The Johnson Research Group: Prof. Jeff Johnson Greg Boyce Geanna Min Dan Schmitt Mike Slade Austin Smith

61. 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.

62. 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.

63. Support of a SET Mechanism in IBX Mediated Dehydrogenations Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258. Hammet analysis shows the reaction is only slightly dependent on the electronics of aryl-containing substrates (ρ= -.75, σ p + )

64. 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.

65. 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.

66. 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.

67. 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.

68. Hydroxylation of Silyl Enol Ethers Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.

69. 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.

70. 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.

71. Reaction is hampered by low conversion Only modest enantioselectivity obtained Progress Towards Asymmetric α- Hydroxylation of Ketones 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.

72. 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.

73. Synthesis of (±)-Cephalotaxine Yasuda, S.; Yamada, T.; Hanoaka, M. Tetrahedron Lett. 1986, 27, 2023-2026.