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
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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 OUTLINE
• Introduction, properties
• Preparation of azides
• Aryl azides
• Alkenyl azides
• Alkyl azides
• Acyl azides
• …
• Reactivity of azides
• Cycloadditions
• Rearrangement
• …
• Conclusion
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
INTRODUCTION 4
• Structure 1d explain the regioselectivity of the reactions with electrophiles (attacked by N1) and nucleophiles (attack on N3)
• Structure 1c explain the facile decomposition into the corresponding nitrene and dinitrogen
• Aromatic azides are stabilized by conjugation with the aromatic system
PREPARATION OF AZIDES 5
1- Synthesis of Azides derivatives
In principle, 5 methods could achieve azide preparation:
1. Insertion of the N3 group (substitution or addition)
2. Insertion of an N2 group (diazo transfer)
3. Insertion of a nitrogen atom (diazotization)
4. Cleavage of triazines and analogous compounds
5. Rearrangement of azides
PREPARATION OF AZIDES 6
1- Aryl AzidesFrom 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
PREPARATION OF AZIDES 7
1- Aryl AzidesFrom Diazonium compounds:
S. M. Capitosti, T. P. Hansen, M. L. Brown, Org. Lett. 2003, 5, 2865 – 2867
Azido-thalidomide
2
PREPARATION OF AZIDES 8
1- Aryl AzidesFrom SNAr Reactions1:
From Organometallic reagents2:
1C. K. Lowe-Ma, R. A. Nissan, W. S. Wilson, J. Org. Chem. 1990, 55, 3755 – 37612J. Gavenonis, T. D. Tilley, Organometallics, 2002, 21, 5549 – 5563
PREPARATION OF AZIDES 9
1- Aryl AzidesFrom Diazo Transfer1:
From Diazotization of Hydrazines3:
Also for alkyl azides2:
:NH2R
1Q. Liu, Y. Tor, Org. Lett. 2003, 5, 2571 – 25722W. S. Horne, C. S. Stout, M. R. Ghadiri, J. Am. Chem. Soc. 2003, 125, 9372 – 93763Y. H. Kim, K. Kim, S. B. Shim, Tetrahedron Lett. 1986, 27, 4749 – 4752
PREPARATION OF AZIDES 10
2- Alkenyl AzidesWith Iodine Azide1:
Addition on an aldehyde2:
1F. W. Fowler, A. Hassner, L. A. Levy, J. Am. Chem. Soc. 1967, 89, 2077 – 20822P. Molina, P. M. Fresneda, S. Delgado, J. Org. Chem. 2003, 68, 489 – 499
PREPARATION OF AZIDES 11
3- Alkyl AzidesNucleophilic substitution:
Asymmetric opening of an epoxide2
1D. Enders, D. Klein, Synlett. 1999, 719 – 7202L. 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 configuration1
PREPARATION OF AZIDES 12
3- Alkyl AzidesBy Mitsunobu reaction:
OP
O
O
N3
Not explosive
1S.-H. Lee, J. Yoon, S.-H. Chung, Y.-S. Lee, Tetrahedron 2001, 57, 2139 – 21452B. Jiang, C.-G. Yang, J. Wang, J. Org. Chem. 2002, 67, 1396 – 1398
Using DPPA:
PREPARATION OF AZIDES 13
3- Alkyl Azides1,4 addition1,2:
1D. J. Guerin, T. E. Horstmann, S. J. Miller, Org. Lett. 1999, 1, 1107 – 11092T. Kawasaki, H. Enoki, K. Matsumura, M. Ohyama, M. Inagawa, M. Sakamoto, Org. Lett. 2000, 2, 3027 – 3029
PREPARATION OF AZIDES 14
3- Alkyl Azides1,2 addition to non-activated double bonds:
Polar1:
Radical2:
1L. Chabaud, Y. Landais, Tetrahedron Lett. 2003, 44, 6995 – 69982M. Tingoli, M. Tiecco, D. Chianelli, R. Balducci, A. Temperini, J. Org. Chem. 1991, 56, 6809 – 6813
PREPARATION OF AZIDES 15
3- Alkyl AzidesC-H activation1 (radical):
Formation of allyl azides2:
1C. Viuf, M. Bols, Angew. Chem. Int. Ed. 2001, 40, 623 – 6252V. Atlan, S. Racouchot, M. Rubin, C. Bremer, J. Ollivier, A. de Meijere, J. SalaQn, Tetrahedron: Asymmetry. 1998, 9, 1131 – 1135
PREPARATION OF AZIDES 16
4- Acyl Azides: Highly reactive, used for the preparation of amides and heterocycles
1B. P. Banddgar, S. S. Pandit, Tetrahedron Lett. 2002, 43, 3413 – 34142A. Padwa, M. A. Brodney, B. Liu, K. Satake, T. Wu, J. Org. Chem. 1999, 64, 3595 – 36073H. Shao, M. Colucci, S. J. Tong, H. S. Zhang, A. L. Castelhano, Tetrahedron Lett. 1998, 39, 7235 – 7238
1F. Avemaria, V. Zimmermann, S. Bräse, Synlett. 2004, 1163 – 11662R. Ducray, M. A. Ciufolini, Angew. Chem. Int. Ed. 2002, 41, 4688 – 4691
1
2
18h, 40ºC75%
AZIDES REACTIVITY 19
1- CycloadditionsTriazolines:
D. S. Reddy,W. R. Judd, J. Aubé, Org. Lett. 2003, 5, 3899 – 3902
TMSOTf
AZIDES REACTIVITY 20
1- CycloadditionsEnantioselective α-sulfamidation via triazolines:
H. Vogt, S. Bräse, unpublished results
AZIDES REACTIVITY 21
1- CycloadditionsTriazoles:
T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6, 2853 – 2855
AZIDES REACTIVITY 22
1- CycloadditionsTetrazoles:
Intermolecular1,2
Intramolecular3
1R. Huisgen, J. Org. Chem. 1968, 33, 2291 – 22972Z. P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945 – 79503Z. P. Demko, K. B. Sharpless, Org. Lett. 2001, 3, 4091 – 4094
AZIDES REACTIVITY 23
1- CycloadditionsTetrazoles: Ugi 4 component reaction
Review: A. Domling, I. Ugi. Angew. Chem. Int. Ed. 2000, 39, 3168-3210
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
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 AZIDES REACTIVITY
Stoechiometric!
2- Nitrene Chemistry: Asymmetric Diels-Alder with chiral ligand
A. S. Timen, P. Somfai, J. Org. Chem. 2003, 68, 9958 – 9963
1S. C. Bergmeier,D. M. Stanchina, J. Org. Chem. 1999, 64, 2852 – 28592Y. Naruta, N. Nagai, K. Maruyama, J. Chem. Soc. Perkin Trans. 1. 1988, 1143 – 1148
1
2
AZIDES REACTIVITY 30
2- Nitrene ChemistryInsertion into sp3 C-H bonds:
1H. Nozaki, S. Fujita, H. Takaya, R. Noyori, Tetrahedron. 1967, 23, 45 – 492D. F. Berndt, P. Norris, Tetrahedron Lett. 2002, 43, 3961 – 39623C. J. Moody, J. G. Ward, J. Chem. Soc. Perkin Trans. 1. 1984, 2895 – 2901
1
2 3
AZIDES REACTIVITY 31
2- Nitrene ChemistryRearrangement of Nitrenes:
1W. L. Karney, W. T. Borden, J. Am. Chem. Soc. 1997, 119, 1378 – 13872K. Knepper, S. Bräse, unpublished results
1P. T. Nyffeler, C.-H. Liang, K. M. Koeller, C.-H. Wong, J. Am. Chem. Soc. 2002, 124, 10 773 – 107782Y. Gaoni, J. Org. Chem. 1994, 59, 6853 – 6855
1
AZIDES REACTIVITY 33
3- Nucleophilic additionAza-Wittig reaction:
AZIDES REACTIVITY 34
3- Nucleophilic additionAza-Wittig reaction:
Humm ???
P. Langer, I. Freifeld, H. Shojaei, Chem. Commun. 2003, 3044 – 3045
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
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
AZIDES REACTIVITY 37
4- Curtius and related rearrangementCurtius rearrangement:
AZIDES REACTIVITY 38
F. M. Menger, J. Bian, V. A. Azov, Angew. Chem. Int. Ed. 2002, 41, 2581 – 2584
4- Curtius and related rearrangementCurtius rearrangement:
AZIDES REACTIVITY 39
Robert T. Yu, Tomislav Rovis, J. Am. Chem. Soc. 2006, ASAP
4- Curtius and related rearrangementCurtius rearrangement:
34-75 %56-70 %
AZIDES REACTIVITY 40
G. F. Alberici, J. Andrieux, G. Adam, M. M. Plat, Tetrahedron Lett. 1983, 24, 1937 – 1940
4- Curtius and related rearrangementSchmidt rearrangement:
AZIDES REACTIVITY 41
5- Reactions of Azides with electrophilesSchmidt and Boyer reactions: Electrophile
L. Kürti, B. Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier Academic Press. 2005, 758 p.
AZIDES REACTIVITY 42
5- Reactions of Azides with electrophilesSchmidt and Boyer reactions:
See Alex Lemire Literature meeting (Nov 8, 2004) for extended explanations
on Aubé’s work
1J. Aubé, G. L. Milligan, J. Am. Chem. Soc. 1991, 113, 8965 – 89662K. Sahasrabudhe, V. Gracias, K. Furness, B. T. Smith, C. E. Katz, S. D. Reddy, J. Aubé, J. Am. Chem. Soc. 2003, 125, 7914 – 7922
AZIDES REACTIVITY 43
5- Reactions of Azides with electrophilesSchmidt and Boyer reactions:
Humm… again!?
S. Lang, A. R. Kennedy, J. A. Murphy, A. H. Payne, Org. Lett. 2003, 5, 3655 – 3658
AZIDES REACTIVITY 44
1S. Rozen, M. Carmeli, J. Am. Chem. Soc. 2003, 125, 8118 – 81192R. Sasson, S. Rozen, Org. Lett, 2005, 7, 2177 - 2179
80% - 98% yieldOn non-functionalized alkyl or aryl
Up to 60% yield
1
2
6- Transformation into nitro and cyano group
AZIDES REACTIVITY 45
7- Radical reactions
1D. S. Hays, G. C. Fu, J. Org. Chem. 1998, 63, 2796 – 27972S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993, 115, 3328 –3329
46
8- Azides for labelling
AZIDES REACTIVITY
Ex: Azido-thalidomide
C. A. Gartner, Curr. Med. Chem. 2003, 10, 671 – 689