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
OUTLINE
• Introduction, properties
• Preparation of azides
• Aryl azides
• Alkenyl azides
• Alkyl azides
• Acyl azides
•…
• Reactivity of azides
• Cycloadditions
• Rearrangement
•…
• Conclusion
2
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 1,3,5triazido-2,4,6-trinitrobenzene*
*D. Adam, PhD Thesis, Ludwigs-Maximillians-Universität München (Germany), 2001
INTRODUCTION
• 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
4
PREPARATION OF AZIDES
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
5
PREPARATION OF AZIDES
1- Aryl Azides
From Diazonium compounds:
Drawback: preparation of the diazonium salt
R. N. Butler, A. Fox, S. Collier, L. A. Burke, J. Chem. Soc. Perkin Trans. 2, 1998, 2243 – 2247
6
PREPARATION OF AZIDES
1- Aryl Azides
From Diazonium compounds:
2
Azido-thalidomide
S. M. Capitosti, T. P. Hansen, M. L. Brown, Org. Lett. 2003, 5, 2865 – 2867
7
PREPARATION OF AZIDES
1- Aryl Azides
From SNAr Reactions1:
From Organometallic reagents2:
1C.
2J.
K. Lowe-Ma, R. A. Nissan, W. S. Wilson, J. Org. Chem. 1990, 55, 3755 – 3761
Gavenonis, T. D. Tilley, Organometallics, 2002, 21, 5549 – 5563
8
PREPARATION OF AZIDES
9
1- Aryl Azides
:NH2R
From Diazo Transfer1:
Also for alkyl azides2:
From Diazotization of Hydrazines3:
Liu, Y. Tor, Org. Lett. 2003, 5, 2571 – 2572
S. Horne, C. S. Stout, M. R. Ghadiri, J. Am. Chem. Soc. 2003, 125, 9372 – 9376
3Y. H. Kim, K. Kim, S. B. Shim, Tetrahedron Lett. 1986, 27, 4749 – 4752
1Q.
2W.
PREPARATION OF AZIDES
2- Alkenyl Azides
With Iodine Azide1:
Addition on an aldehyde2:
1F.
2P.
W. Fowler, A. Hassner, L. A. Levy, J. Am. Chem. Soc. 1967, 89, 2077 – 2082
Molina, P. M. Fresneda, S. Delgado, J. Org. Chem. 2003, 68, 489 – 499
10
PREPARATION OF AZIDES
3- Alkyl Azides
Nucleophilic substitution:
Substitution of an iodo atom with
retention of configuration1
Asymmetric opening of an epoxide2
1D.
2L.
Enders, D. Klein, Synlett. 1999, 719 – 720
E. Martínez, J. L. Leighton, D. H. Carsten, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5897 – 5898
11
PREPARATION OF AZIDES
3- Alkyl Azides
By Mitsunobu reaction:
O
Using DPPA:
O
P
N3
O
Not explosive
Lee, J. Yoon, S.-H. Chung, Y.-S. Lee, Tetrahedron 2001, 57, 2139 – 2145
Jiang, C.-G. Yang, J. Wang, J. Org. Chem. 2002, 67, 1396 – 1398
1S.-H.
2B.
12
PREPARATION OF AZIDES
3- Alkyl Azides
1,4 addition1,2:
1D.
2T.
J. Guerin, T. E. Horstmann, S. J. Miller, Org. Lett. 1999, 1, 1107 – 1109
Kawasaki, H. Enoki, K. Matsumura, M. Ohyama, M. Inagawa, M. Sakamoto, Org. Lett. 2000, 2, 3027 – 3029
13
PREPARATION OF AZIDES
3- Alkyl Azides
1,2 addition to non-activated double bonds:
Polar1:
Radical2:
1L.
2M.
Chabaud, Y. Landais, Tetrahedron Lett. 2003, 44, 6995 – 6998
Tingoli, M. Tiecco, D. Chianelli, R. Balducci, A. Temperini, J. Org. Chem. 1991, 56, 6809 – 6813
14
PREPARATION OF AZIDES
15
3- Alkyl Azides
C-H activation1 (radical):
Formation of allyl azides2:
1C.
2V.
Viuf, M. Bols, Angew. Chem. Int. Ed. 2001, 40, 623 – 625
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
1
71%-94%
2
3
P. Banddgar, S. S. Pandit, Tetrahedron Lett. 2002, 43, 3413 – 3414
Padwa, M. A. Brodney, B. Liu, K. Satake, T. Wu, J. Org. Chem. 1999, 64, 3595 – 3607
3H. Shao, M. Colucci, S. J. Tong, H. S. Zhang, A. L. Castelhano, Tetrahedron Lett. 1998, 39, 7235 – 7238
1B.
2A.
AZIDES REACTIVITY
2- Reactions involving azides
17
AZIDES REACTIVITY
1- Cycloadditions
Triazolines:
1
18h, 40ºC
75%
2
Strained olefins and alkynes reacts readily, terminal alkenes react extremely slowly
1F.
2R.
Avemaria, V. Zimmermann, S. Bräse, Synlett. 2004, 1163 – 1166
Ducray, M. A. Ciufolini, Angew. Chem. Int. Ed. 2002, 41, 4688 – 4691
18
AZIDES REACTIVITY
1- Cycloadditions
Triazolines:
D. S. Reddy,W. R. Judd, J. Aubé, Org. Lett. 2003, 5, 3899 – 3902
TMSOTf
19
AZIDES REACTIVITY
1- Cycloadditions
Enantioselective α-sulfamidation via triazolines:
H. Vogt, S. Bräse, unpublished results
20
AZIDES REACTIVITY
1- Cycloadditions
Triazoles:
T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6, 2853 – 2855
21
AZIDES REACTIVITY
1- Cycloadditions
Tetrazoles:
Intermolecular1,2
Intramolecular3
Huisgen, J. Org. Chem. 1968, 33, 2291 – 2297
P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945 – 7950
3Z. P. Demko, K. B. Sharpless, Org. Lett. 2001, 3, 4091 – 4094
1R.
2Z.
22
AZIDES REACTIVITY
1- Cycloadditions
Tetrazoles: Ugi 4 component reaction
Review: A. Domling, I. Ugi. Angew. Chem. Int. Ed. 2000, 39, 3168-3210
23
AZIDES REACTIVITY
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
24
AZIDES REACTIVITY
2- Nitrene Chemistry: Asymmetric Diels-Alder with chiral auxiliary
A. S. Timen, P. Somfai, J. Org. Chem. 2003, 68, 9958 – 9963
25
AZIDES REACTIVITY
2- Nitrene Chemistry: Asymmetric Diels-Alder with chiral ligand
Stoechiometric!
A. S. Timen, P. Somfai, J. Org. Chem. 2003, 68, 9958 – 9963
26
AZIDES REACTIVITY
2- Nitrene Chemistry
Intramolecular cycloadditions:
27
AZIDES REACTIVITY
2- Nitrene Chemistry
Intramolecular cycloadditions:
Biazirinyls synthesis
K. Banert, F. KPhler, Angew. Chem. Int. Ed. 2001, 40, 174 – 177
28
AZIDES REACTIVITY
2- Nitrene Chemistry
Intramolecular cycloadditions:
1
2
via
1S.
2Y.
C. Bergmeier,D. M. Stanchina, J. Org. Chem. 1999, 64, 2852 – 2859
Naruta, N. Nagai, K. Maruyama, J. Chem. Soc. Perkin Trans. 1. 1988, 1143 – 1148
29
AZIDES REACTIVITY
2- Nitrene Chemistry
Insertion into sp3 C-H bonds:
1
2
3
Nozaki, S. Fujita, H. Takaya, R. Noyori, Tetrahedron. 1967, 23, 45 – 49
F. Berndt, P. Norris, Tetrahedron Lett. 2002, 43, 3961 – 3962
3C. J. Moody, J. G. Ward, J. Chem. Soc. Perkin Trans. 1. 1984, 2895 – 2901
1H.
2D.
30
AZIDES REACTIVITY
2- Nitrene Chemistry
Rearrangement of Nitrenes:
1
2
1W.
2K.
L. Karney, W. T. Borden, J. Am. Chem. Soc. 1997, 119, 1378 – 1387
Knepper, S. Bräse, unpublished results
31
AZIDES REACTIVITY
3- Nucleophilic addition
The Staudinger reduction:
:PR3
1
Hydrogenation2:
1P.
2Y.
T. Nyffeler, C.-H. Liang, K. M. Koeller, C.-H. Wong, J. Am. Chem. Soc. 2002, 124, 10 773 – 10778
Gaoni, J. Org. Chem. 1994, 59, 6853 – 6855
32
AZIDES REACTIVITY
3- Nucleophilic addition
Aza-Wittig reaction:
33
AZIDES REACTIVITY
3- Nucleophilic addition
Aza-Wittig reaction:
Humm ???
P. Langer, I. Freifeld, H. Shojaei, Chem. Commun. 2003, 3044 – 3045
34
AZIDES REACTIVITY
3- Nucleophilic addition
The iminophosphorane can also react with other electrophiles (ex: epoxides)
In that case, an azetidine was created under Staudinger conditions
S. Obika, J.-i. Andoh, M. Onoda, O. Nakagawa, A. Hiroto, T. Sugimoto, T. Imanishi, Tetrahedron Lett. 2003, 44, 5267 – 5270
35
AZIDES REACTIVITY
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
36
AZIDES REACTIVITY
4- Curtius and related rearrangement
Curtius rearrangement:
37
AZIDES REACTIVITY
4- Curtius and related rearrangement
Curtius rearrangement:
F. M. Menger, J. Bian, V. A. Azov, Angew. Chem. Int. Ed. 2002, 41, 2581 – 2584
38
AZIDES REACTIVITY
39
4- Curtius and related rearrangement
Curtius rearrangement:
34-75 %
56-70 %
Robert T. Yu, Tomislav Rovis, J. Am. Chem. Soc. 2006, ASAP
AZIDES REACTIVITY
4- Curtius and related rearrangement
Schmidt rearrangement:
G. F. Alberici, J. Andrieux, G. Adam, M. M. Plat, Tetrahedron Lett. 1983, 24, 1937 – 1940
40
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.
AZIDES REACTIVITY
5- Reactions of Azides with electrophiles
Schmidt and Boyer reactions:
42
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 – 8966
2K.
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
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
43
AZIDES REACTIVITY
6- Transformation into nitro and
cyano group
1
80% - 98% yield
On non-functionalized alkyl or aryl
2
Up to 60% yield
1S.
2R.
Rozen, M. Carmeli, J. Am. Chem. Soc. 2003, 125, 8118 – 8119
Sasson, S. Rozen, Org. Lett, 2005, 7, 2177 - 2179
44
AZIDES REACTIVITY
7- Radical reactions
1D.
2S.
S. Hays, G. C. Fu, J. Org. Chem. 1998, 63, 2796 – 2797
Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993, 115, 3328 –3329
45
AZIDES REACTIVITY
8- Azides for labelling
Ex: Azido-thalidomide
C. A. Gartner, Curr. Med. Chem. 2003, 10, 671 – 689
46
CONCLUSION
47
Examples, from my bench…
DPPA:
CONCLUSION
Airbags… A useful application of azides
48