An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles

Marko Kljajic, Rolf Breinbauer

Research output: Contribution to conferencePosterResearch

Abstract

We are currently investigating the effect of ligand properties on the Tsuji-Trost reaction to enable a method for the activation of various heterocycles with high pKas. Several groups have demonstrated the activation of pronucleophiles with pKas higher than 30, but the use of Lewis acids or strong bases as additives remained necessary.[1-6] In our approach we envisioned to enable a base- and additive-free allylic alkylation of such pronucleophiles. Eventually we were able to identify a ligand/precatalyst system which enabled the additive-free allylic alkylation of nitrogen heterocycles under mild conditions using allyl acetate as reagent even under protic conditions. This new methodology may facilitate a late stage modification of pharmaceuticals and base sensitive substrates in comparison to other known methods. Additional mechanistic investigations suggest a formal [3,3] Aza-Claisen rearrangement as one of the key steps towards the desired products.
[1] Trost. B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092–14093.
[2] Trost. B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2009, 131, 12056-12057.
[3] Trost, B. M.; Thaisrivongs, D. A.; Hartwig, J. J. Am. Chem. Soc. 2011, 133, 12439-12441.
[4] Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 1360-1363.
[5] Zhang, J.; Stanciu, C.; Wang, B.; Hussain, M. M.; Da, C.-S.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc. 2011, 133, 20552–20560.
[6] Sha, S.-C.; Zhang, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2013, 135, 17602-17609.
Original languageEnglish
Publication statusPublished - 30 Jun 2016
EventTetrahedron Symposium - Barcelona, Barcelona, Spain
Duration: 28 Jun 20161 Jul 2016

Conference

ConferenceTetrahedron Symposium
CountrySpain
CityBarcelona
Period28/06/161/07/16

Fingerprint

Nitrogen
Activation
Pharmaceuticals
Rearrangement
Substrate
Necessary
Methodology

Cite this

Kljajic, M., & Breinbauer, R. (2016). An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles. Poster session presented at Tetrahedron Symposium, Barcelona, Spain.

An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles. / Kljajic, Marko; Breinbauer, Rolf.

2016. Poster session presented at Tetrahedron Symposium, Barcelona, Spain.

Research output: Contribution to conferencePosterResearch

Kljajic, M & Breinbauer, R 2016, 'An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles' Tetrahedron Symposium, Barcelona, Spain, 28/06/16 - 1/07/16, .
Kljajic M, Breinbauer R. An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles. 2016. Poster session presented at Tetrahedron Symposium, Barcelona, Spain.
Kljajic, Marko ; Breinbauer, Rolf. / An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles. Poster session presented at Tetrahedron Symposium, Barcelona, Spain.
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AB - We are currently investigating the effect of ligand properties on the Tsuji-Trost reaction to enable a method for the activation of various heterocycles with high pKas. Several groups have demonstrated the activation of pronucleophiles with pKas higher than 30, but the use of Lewis acids or strong bases as additives remained necessary.[1-6] In our approach we envisioned to enable a base- and additive-free allylic alkylation of such pronucleophiles. Eventually we were able to identify a ligand/precatalyst system which enabled the additive-free allylic alkylation of nitrogen heterocycles under mild conditions using allyl acetate as reagent even under protic conditions. This new methodology may facilitate a late stage modification of pharmaceuticals and base sensitive substrates in comparison to other known methods. Additional mechanistic investigations suggest a formal [3,3] Aza-Claisen rearrangement as one of the key steps towards the desired products.[1] Trost. B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092–14093.[2] Trost. B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2009, 131, 12056-12057.[3] Trost, B. M.; Thaisrivongs, D. A.; Hartwig, J. J. Am. Chem. Soc. 2011, 133, 12439-12441.[4] Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 1360-1363.[5] Zhang, J.; Stanciu, C.; Wang, B.; Hussain, M. M.; Da, C.-S.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc. 2011, 133, 20552–20560.[6] Sha, S.-C.; Zhang, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2013, 135, 17602-17609.

M3 - Poster

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