1. Organic Azides, an Overview Their synthesis, reactions and applications Literature Meeting / February 13, 2006 Guillaume Larouche Under supervision of Prof. André B. Charette Based, in part, on the review: Organic Azides: An Exploding Diversity of a Unique Class of Compounds Stefan Bräse, Carmen Gil, Kerstin Knepper and Viktor Zimmerman Angew. Chem. Int. Ed. 2005, 44, 5188-5240

2. 2 OUTLINE Introduction, properties Preparation of azides Aryl azides Alkenyl azides Alkyl azides Acyl azides … Reactivity of azides Cycloadditions Rearrangement … Conclusion

3. INTRODUCTION 3 Prepared first by Peter Grieß in 1864 (phenyl azide) followed by Curtius (hydrogen azide) 1H-triazirine was the proposed structure which was rapidly revised in favor of the linear model Most azides are explosive substances which decompose with the release of nitrogen ORTEP representation of 1,3,5- triazido-2,4,6-trinitrobenzene* *D. Adam, PhD Thesis, Ludwigs-Maximillians-Universität München (Germany), 2001

4. INTRODUCTION 4 Structure 1d explain the regioselectivity of the reactions with electrophiles (attacked by N 1 ) and nucleophiles (attack on N 3 ) Structure 1c explain the facile decomposition into the corresponding nitrene and dinitrogen Aromatic azides are stabilized by conjugation with the aromatic system

5. PREPARATION OF AZIDES 5 1- Synthesis of Azides derivatives In principle, 5 methods could achieve azide preparation: 1.Insertion of the N 3 group (substitution or addition) 2.Insertion of an N 2 group (diazo transfer) 3.Insertion of a nitrogen atom (diazotization) 4.Cleavage of triazines and analogous compounds 5.Rearrangement of azides

6. PREPARATION OF AZIDES 6 1- Aryl Azides From Diazonium compounds: R. N. Butler, A. Fox, S. Collier, L. A. Burke, J. Chem. Soc. Perkin Trans. 2, 1998, 2243 – 2247 Drawback: preparation of the diazonium salt

7. PREPARATION OF AZIDES 7 1- Aryl Azides From Diazonium compounds: S. M. Capitosti, T. P. Hansen, M. L. Brown, Org. Lett. 2003, 5, 2865 – 2867 Azido-thalidomide 2

8. PREPARATION OF AZIDES 8 1- Aryl Azides From S N Ar Reactions 1 : From Organometallic reagents 2 : 1 C. K. Lowe-Ma, R. A. Nissan, W. S. Wilson, J. Org. Chem. 1990, 55, 3755 – 3761 2 J. Gavenonis, T. D. Tilley, Organometallics, 2002, 21, 5549 – 5563

9. PREPARATION OF AZIDES 9 1- Aryl Azides From Diazo Transfer 1 : From Diazotization of Hydrazines 3 : Also for alkyl azides 2 : :NH 2 R 1 Q. Liu, Y. Tor, Org. Lett. 2003, 5, 2571 – 2572 2 W. S. Horne, C. S. Stout, M. R. Ghadiri, J. Am. Chem. Soc. 2003, 125, 9372 – 9376 3 Y. H. Kim, K. Kim, S. B. Shim, Tetrahedron Lett. 1986, 27, 4749 – 4752

10. PREPARATION OF AZIDES 10 2- Alkenyl Azides With Iodine Azide 1 : Addition on an aldehyde 2 : 1 F. W. Fowler, A. Hassner, L. A. Levy, J. Am. Chem. Soc. 1967, 89, 2077 – 2082 2 P. Molina, P. M. Fresneda, S. Delgado, J. Org. Chem. 2003, 68, 489 – 499

11. PREPARATION OF AZIDES 11 3- Alkyl Azides Nucleophilic substitution: Asymmetric opening of an epoxide 2 1 D. Enders, D. Klein, Synlett. 1999, 719 – 720 2 L. E. Martínez, J. L. Leighton, D. H. Carsten, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5897 – 5898 Substitution of an iodo atom with retention of configuration 1

12. PREPARATION OF AZIDES 12 3- Alkyl Azides By Mitsunobu reaction: Not explosive 1 S.-H. Lee, J. Yoon, S.-H. Chung, Y.-S. Lee, Tetrahedron 2001, 57, 2139 – 2145 2 B. Jiang, C.-G. Yang, J. Wang, J. Org. Chem. 2002, 67, 1396 – 1398 Using DPPA:

13. PREPARATION OF AZIDES 13 3- Alkyl Azides 1,4 addition 1,2 : 1 D. J. Guerin, T. E. Horstmann, S. J. Miller, Org. Lett. 1999, 1, 1107 – 1109 2 T. Kawasaki, H. Enoki, K. Matsumura, M. Ohyama, M. Inagawa, M. Sakamoto, Org. Lett. 2000, 2, 3027 – 3029

14. PREPARATION OF AZIDES 14 3- Alkyl Azides 1,2 addition to non-activated double bonds: Polar 1 : Radical 2 : 1 L. Chabaud, Y. Landais, Tetrahedron Lett. 2003, 44, 6995 – 6998 2 M. Tingoli, M. Tiecco, D. Chianelli, R. Balducci, A. Temperini, J. Org. Chem. 1991, 56, 6809 – 6813

15. PREPARATION OF AZIDES 15 3- Alkyl Azides C-H activation 1 (radical): Formation of allyl azides 2 : 1 C. Viuf, M. Bols, Angew. Chem. Int. Ed. 2001, 40, 623 – 625 2 V. Atlan, S. Racouchot, M. Rubin, C. Bremer, J. Ollivier, A. de Meijere, J. SalaQn, Tetrahedron: Asymmetry. 1998, 9, 1131 – 1135

16. PREPARATION OF AZIDES 16 4- Acyl Azides: Highly reactive, used for the preparation of amides and heterocycles 1 B. P. Banddgar, S. S. Pandit, Tetrahedron Lett. 2002, 43, 3413 – 3414 2 A. Padwa, M. A. Brodney, B. Liu, K. Satake, T. Wu, J. Org. Chem. 1999, 64, 3595 – 3607 3 H. Shao, M. Colucci, S. J. Tong, H. S. Zhang, A. L. Castelhano, Tetrahedron Lett. 1998, 39, 7235 – 7238 1 2 3 71%-94%

17. AZIDES REACTIVITY 17 2- Reactions involving azides

18. AZIDES REACTIVITY 18 1- Cycloadditions Triazolines: Strained olefins and alkynes reacts readily, terminal alkenes react extremely slowly 1 F. Avemaria, V. Zimmermann, S. Bräse, Synlett. 2004, 1163 – 1166 2 R. Ducray, M. A. Ciufolini, Angew. Chem. Int. Ed. 2002, 41, 4688 – 4691 1 2 18h, 40ºC 75%

19. AZIDES REACTIVITY 19 1- Cycloadditions Triazolines: D. S. Reddy,W. R. Judd, J. Aubé, Org. Lett. 2003, 5, 3899 – 3902 TMSOTf

20. AZIDES REACTIVITY 20 1- Cycloadditions Enantioselective α-sulfamidation via triazolines: H. Vogt, S. Bräse, unpublished results

21. AZIDES REACTIVITY 21 1- Cycloadditions Triazoles: T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6, 2853 – 2855

22. AZIDES REACTIVITY 22 1- Cycloadditions Tetrazoles: Intermolecular 1,2 Intramolecular 3 1 R. Huisgen, J. Org. Chem. 1968, 33, 2291 – 2297 2 Z. P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945 – 7950 3 Z. P. Demko, K. B. Sharpless, Org. Lett. 2001, 3, 4091 – 4094

23. AZIDES REACTIVITY 23 1- Cycloadditions Tetrazoles: Ugi 4 component reaction Review: A. Domling, I. Ugi. Angew. Chem. Int. Ed. 2000, 39, 3168-3210

24. AZIDES REACTIVITY 24 2- Nitrene Chemistry Azides can generate nitrenes thermally or photochemically Formation of 2H-azirines Y. S. P. alvarez, M. J. Alves, N. Z. Azoia, J. F. Bickley, T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1. 2002, 1911 – 1919

25. A. S. Timen, P. Somfai, J. Org. Chem. 2003, 68, 9958 – 9963 AZIDES REACTIVITY 25 2- Nitrene Chemistry: Asymmetric Diels-Alder with chiral auxiliary

26. 26 AZIDES REACTIVITY Stoechiometric! 2- Nitrene Chemistry: Asymmetric Diels-Alder with chiral ligand A. S. Timen, P. Somfai, J. Org. Chem. 2003, 68, 9958 – 9963

27. AZIDES REACTIVITY 27 2- Nitrene Chemistry Intramolecular cycloadditions:

28. AZIDES REACTIVITY 28 2- Nitrene Chemistry Intramolecular cycloadditions: K. Banert, F. KPhler, Angew. Chem. Int. Ed. 2001, 40, 174 – 177 Biazirinyls synthesis

29. AZIDES REACTIVITY 29 2- Nitrene Chemistry Intramolecular cycloadditions: via 1 S. C. Bergmeier,D. M. Stanchina, J. Org. Chem. 1999, 64, 2852 – 2859 2 Y. Naruta, N. Nagai, K. Maruyama, J. Chem. Soc. Perkin Trans. 1. 1988, 1143 – 1148 1 2

30. AZIDES REACTIVITY 30 2- Nitrene Chemistry Insertion into sp 3 C-H bonds: 1 H. Nozaki, S. Fujita, H. Takaya, R. Noyori, Tetrahedron. 1967, 23, 45 – 49 2 D. F. Berndt, P. Norris, Tetrahedron Lett. 2002, 43, 3961 – 3962 3 C. J. Moody, J. G. Ward, J. Chem. Soc. Perkin Trans. 1. 1984, 2895 – 2901 1 23

31. AZIDES REACTIVITY 31 2- Nitrene Chemistry Rearrangement of Nitrenes: 1 W. L. Karney, W. T. Borden, J. Am. Chem. Soc. 1997, 119, 1378 – 1387 2 K. Knepper, S. Bräse, unpublished results 1 2

32. AZIDES REACTIVITY 32 3- Nucleophilic addition The Staudinger reduction: :PR 3 Hydrogenation 2 : 1 P. T. Nyffeler, C.-H. Liang, K. M. Koeller, C.-H. Wong, J. Am. Chem. Soc. 2002, 124, 10 773 – 10778 2 Y. Gaoni, J. Org. Chem. 1994, 59, 6853 – 6855 1

33. AZIDES REACTIVITY 33 3- Nucleophilic addition Aza-Wittig reaction:

34. AZIDES REACTIVITY 34 3- Nucleophilic addition Aza-Wittig reaction: Humm ??? P. Langer, I. Freifeld, H. Shojaei, Chem. Commun. 2003, 3044 – 3045

35. The iminophosphorane can also react with other electrophiles (ex: epoxides) In that case, an azetidine was created under Staudinger conditions AZIDES REACTIVITY 35 3- Nucleophilic addition S. Obika, J.-i. Andoh, M. Onoda, O. Nakagawa, A. Hiroto, T. Sugimoto, T. Imanishi, Tetrahedron Lett. 2003, 44, 5267 – 5270

36. AZIDES REACTIVITY 36 3- Nucleophilic addition Improved diazo transer method developed in the group R. P. Wurz, W. Lin, A. B. Charette, Tetrahedron Lett. 2003, 44, 8845 – 8848

37. AZIDES REACTIVITY 37 4- Curtius and related rearrangement Curtius rearrangement:

38. AZIDES REACTIVITY 38 F. M. Menger, J. Bian, V. A. Azov, Angew. Chem. Int. Ed. 2002, 41, 2581 – 2584 4- Curtius and related rearrangement Curtius rearrangement:

39. AZIDES REACTIVITY 39 Robert T. Yu, Tomislav Rovis, J. Am. Chem. Soc. 2006, ASAP 4- Curtius and related rearrangement Curtius rearrangement: 34-75 % 56-70 %

40. AZIDES REACTIVITY 40 G. F. Alberici, J. Andrieux, G. Adam, M. M. Plat, Tetrahedron Lett. 1983, 24, 1937 – 1940 4- Curtius and related rearrangement Schmidt rearrangement:

41. AZIDES REACTIVITY 41 5- Reactions of Azides with electrophiles Schmidt and Boyer reactions: Electrophile L. Kürti, B. Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier Academic Press. 2005, 758 p.

42. AZIDES REACTIVITY 42 5- Reactions of Azides with electrophiles Schmidt and Boyer reactions: See Alex Lemire Literature meeting (Nov 8, 2004) for extended explanations on Aubé’s work 1 J. Aubé, G. L. Milligan, J. Am. Chem. Soc. 1991, 113, 8965 – 8966 2 K. Sahasrabudhe, V. Gracias, K. Furness, B. T. Smith, C. E. Katz, S. D. Reddy, J. Aubé, J. Am. Chem. Soc. 2003, 125, 7914 – 7922

43. AZIDES REACTIVITY 43 5- Reactions of Azides with electrophiles Schmidt and Boyer reactions: Humm… again!? S. Lang, A. R. Kennedy, J. A. Murphy, A. H. Payne, Org. Lett. 2003, 5, 3655 – 3658

44. AZIDES REACTIVITY 44 1 S. Rozen, M. Carmeli, J. Am. Chem. Soc. 2003, 125, 8118 – 8119 2 R. Sasson, S. Rozen, Org. Lett, 2005, 7, 2177 - 2179 80% - 98% yield On non-functionalized alkyl or aryl Up to 60% yield 1 2 6- Transformation into nitro and cyano group

45. AZIDES REACTIVITY 45 7- Radical reactions 1 D. S. Hays, G. C. Fu, J. Org. Chem. 1998, 63, 2796 – 2797 2 S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993, 115, 3328 –3329

46. 46 8- Azides for labelling AZIDES REACTIVITY Ex: Azido-thalidomide C. A. Gartner, Curr. Med. Chem. 2003, 10, 671 – 689

47. CONCLUSION 47 Examples, from my bench… DPPA:

48. CONCLUSION 48 Airbags… A useful application of azides