Organic Azides, an Overview Their synthesis, reactions and applications

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


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


1- Aryl AzidesFrom Diazonium compounds:

S. M. Capitosti, T. P. Hansen, M. L. Brown, Org. Lett. 2003, 5, 2865 – 2867

Azido-thalidomide

2


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


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


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


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


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:


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


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


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


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

1

2

3

71%-94%

AZIDES REACTIVITY 17

2- Reactions involving azides


1- CycloadditionsTriazolines:

Strained olefins and alkynes reacts readily, terminal alkenes react extremely slowly

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%


1- CycloadditionsTriazolines:

D. S. Reddy,W. R. Judd, J. Aubé, Org. Lett. 2003, 5, 3899 – 3902

TMSOTf


1- CycloadditionsEnantioselective α-sulfamidation via triazolines:

H. Vogt, S. Bräse, unpublished results


1- CycloadditionsTriazoles:

T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6, 2853 – 2855


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


1- CycloadditionsTetrazoles: Ugi 4 component reaction

Review: A. Domling, I. Ugi. Angew. Chem. Int. Ed. 2000, 39, 3168-3210


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


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


2- Nitrene ChemistryIntramolecular cycloadditions:



K. Banert, F. KPhler, Angew. Chem. Int. Ed. 2001, 40, 174 – 177

Biazirinyls synthesis



via

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


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


2- Nitrene ChemistryRearrangement of Nitrenes:

1W. L. Karney, W. T. Borden, J. Am. Chem. Soc. 1997, 119, 1378 – 13872K. Knepper, S. Bräse, unpublished results

1

2


3- Nucleophilic additionThe Staudinger reduction: :PR3

Hydrogenation2:

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


3- Nucleophilic additionAza-Wittig reaction:


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


3- Nucleophilic addition

S. Obika, J.-i. Andoh, M. Onoda, O. Nakagawa, A. Hiroto, T. Sugimoto, T. Imanishi, Tetrahedron Lett. 2003, 44, 5267 – 5270


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


4- Curtius and related rearrangementCurtius rearrangement:


F. M. Menger, J. Bian, V. A. Azov, Angew. Chem. Int. Ed. 2002, 41, 2581 – 2584



Robert T. Yu, Tomislav Rovis, J. Am. Chem. Soc. 2006, ASAP


34-75 %56-70 %


G. F. Alberici, J. Andrieux, G. Adam, M. M. Plat, Tetrahedron Lett. 1983, 24, 1937 – 1940

4- Curtius and related rearrangementSchmidt rearrangement:


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.


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


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


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


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

CONCLUSION 47

Examples, from my bench…DPPA:

CONCLUSION 48

Airbags… A useful application of azides

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Organic Azides, an Overview Their synthesis, reactions and applications