The Schmidt and Boyer Reactions Revisited: The Chemistry of Prof. Jeffrey Aubé

1. The Schmidt and Boyer Reactions Revisited: The Chemistry of Prof. Jeffrey Aubé Alexandre Lemire Litterature Meeting November 8th, 2004

2. Prof. Jeffrey Aubé University of Kansas • Interim Chair, 2003 - present • Professor, 1996 – present • Associate Professor, 1992 -1996 • Assistant Professor, 1986 -1992 • Olin Petefish/Higuchi Award for Achievement in the Basic Sciences, 2001 • Fellow, Japanese Society for the Promotion of Science, 1996 • Phi Beta Kappa, honorary member, 1996 • American Cyanamid Faculty Award in Organic Chemistry, 1993 • Alfred P. Sloan Research Fellow, 1993 -1995 • Eli Lilly Grantee, 1989 -1991 Department of Medicinal ChemistrySchool of PharmacyUniversity of KansasLawrence, Kansas 66045-2506Tel: 1.785.864.4496 Fax: 1.785.864.5326e-mail: jaube@ku.edu

3. Prof. Jeffrey Aubé 85 publications • NIS Postdoctoral fellow 1984-1986 Yale U. (Prof. Danishefsky) • PhD Duke University 1984 (Durham, NC) • BSc U. of Miami 1980 Department of Medicinal ChemistrySchool of PharmacyUniversity of KansasLawrence, Kansas 66045-2506Tel: 1.785.864.4496 Fax: 1.785.864.5326e-mail: jaube@ku.edu

4. The Schmidt Reaction (1) Name Reaction in Organic Chemistry, p. 190-191 Schmidt, R. F. Ber.1924, 57, 704. Reviews: (a) Wolff, H. Org. React.1946, 3, 307-336. (b) Krow, G. R. Tetrahedron1981, 37, 1283-1307.

5. Mechanism?

6. The Schmidt Reaction (2) The Merck Index, 12th Edition, p. ONR-82

7. The Schmidt Reaction (2)

8. Analogous Rearrangements

9. Reactions with Alkyl Azides

10. Reactions with Alkyl Azides 1 (a) Briggs, L. H. et al.J. Chem. Soc.1942, 61-63. (b) Smith, P. A. J. Am. Chem. Soc.1948, 70, 320-323. 2 Boyer, J. H. et al. J. Am. Chem. Soc.1956, 78, 325-327. Boyer, J. H.; Morgan, L. R., Jr. J. Am. Chem. Soc.1959, 81, 561-562.

11. Aubé and Milligan’s Discovery Communication: J. Am. Chem. Soc.1991, 113, 8965-8966. Full paper: J. Am. Chem. Soc.1995, 117, 10449-10459.

12. Aubé and Milligan’s Discovery

13. Questions to address • Effects of ring size and tether length • Reaction conditions to effectively promote the process • Regiochemical rules to predict the product of the intramolecular Schmidt reaction • Stereochemistry (retention or inversion) at the migrating carbon

14. Effect of ring size and tether length pyrrolizidine quinolizidine indolizidine 90% SM recovery after 1 h! (stability of azide in TFA)

15. Effect of ring size and tether length TiCl4 can help with recalcitrant substrates but not always

16. Effect of ring size and tether length Results inconsistent with a mechanism implying a nitrene or nitrenium species: given their high reactivity, their formation would be rate limiting and they would not be affected by structural change near the carbonyl group 4 carbons away The most readily accomplished ring-expansion reactions involved substrates containing 4 carbons between the carbonyl group and the azido substitutent. The reaction proceeds through a presumably optimal six-membered cyclic azidohydrin intermediate previously shown Formation of the five-membered azidohydrin should be facile, but the reaction fails, presumably due to strain encountered en route to the expected azetidine product Ring expansion of aromatic ketones are less efficient:

17. Regiochemistry Theoritical and experimental insights support a mechanism were the proximal nitrogen atom of the aminodiazonium ion intermediate has appreciable tetrahedral character in the transition state leading to product. Chairlike azidohydrins are likely achieved when possible and migration of an antiperiplanar substituent during nitrogen loss leads to four possible intermediates:

18. Regiochemistry antiperiplanar C-C bond migration Only intermediate d has a pseudoaxial N2+ moiety, wich leads to bridged product. This intermediate might lead to an higher energy transition state so the corresponding product is not observed Another explanation is that the bridged bicyclic amide is not accessible because of the instability of the amide linkage In the acyclic series, this would not be an issue anymore:

19. Regiochemistry: Acyclic Ketones antiperiplanar C-C bond migration The population of azidohydrin type c would be expected to increase with smaller R1 substituents, like H

20. Regiochemistry: Acyclic Substrates No azetidine formed, pyrrolidinone occurred only from aldehydes

21. Regiochemistry: Acyclic Substrates Again, lactams only observed when aldehydes are reacted Possibly because only H is small enough to permit path c discussed

22. Regiochemistry: Acyclic Aldehydes Another mechanism could explain the formation of these lactams H migration has been rarely observed, the elimination/tautomerization pathway is though to be favored

23. Stereochemistry of the Migrating Carbon Note that we can deprotect the carbonyl group without triggering the intramolecular Schmidt reaction Ring expansion occurred with retention of configuration, as known for the intermolecular process (HN3):

24. Stereochemistry of the Migrating Carbon The classical Schmidt affords also the regioisomer and tetrazole byproduct The major compound forms the lactam with identical ee

25. Stereochemistry of the Migrating Carbon: Enolizable Ketone Little isomerization occurred with TFA for the trans ketone Can be avoided using TiCl4/CH2Cl2

26. Stereochemistry of the Migrating Carbon

28. Ring Expansion of Alkyl Azides to Ketones Boyer, J. H. et al. J. Am. Chem. Soc.1956, 78, 325-327.

29. Ring Expansion of Alkyl Azides to Ketones Communication: J. Org. Chem.1992, 57, 1635-1637. Full paper: J. Am. Chem. Soc.2000, 122, 7226-7232. Follow up: J. Org. Chem.2001, 66, 886-889.

30. Ring Expansion of Alkyl Azides to Ketones

31. Ring Expansion of Alkyl Azides to Ketones Reaction using BF3OEt2 or protic acids failed Unindered cyclohexanones and cyclobutanone are successful Unsymmetrical ketones gave mixtures of lactams Only BnN3 and HexN3 reported

33. ???

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35. Use of TfOH: Mechanism

36. Use of TfOH

38. Ring Expansion of Hydroxy Azides to Ketones: The Boyer Reaction Boyer, J. H. et al. J. Am. Chem. Soc.1956, 78, 325-327. Boyer, J. H.; Morgan, L. R., Jr. J. Am. Chem. Soc.1959, 81, 561-562.

39. The Boyer Reaction Revisited by Aubé Communication: J. Am. Chem. Soc.1995, 117, 8047-8048. Follow up: J. Org. Chem.1996, 61, 2484-2487. Full paper: Tetrahedron1997, 53, 16241-16252. Related paper: J. Org. Chem.2000, 65, 3771-3774.

40. Mechanism Mechanism originally proposed by Boyer

41. Mechanism Mechanism seems more reasonable in light of relative easyness of intramolecular Schmidt reaction

42. Bronsted and Lewis Acid Survey

43. Azide Tether Length

44. Azide Tether Length 2 or 3 C between OH and N3 is optimal Longer alkyl chain leads to transient formation of a seven or higher-membered ring system This leads to the shift in mechanism shown above, to the original proposal of Boyer These behave as simple alkyl azides

45. Mechanism

46. Symmetrical Ketones

47. Unsymmetrical Ketones

49. Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones:Desymetrization of meso-Ketones Communication: Org. Lett.1999, 1, 495-497. Full paper: J. Am. Chem. Soc.2003, 125, 7914-7922. Follow up: J. Am. Chem. Soc.2003, 125, 13948-13949. Theoritical studies: J. Org. Chem.2004, 69, 3439-3446.

50. Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones