TY - CONF
T1 - An Additive-Free Approach for the Alpha-Allylation of Nitrogen Heterocycles
AU - Kljajic, Marko
AU - Breinbauer, Rolf
PY - 2016/6/30
Y1 - 2016/6/30
N2 - 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.
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
T2 - Tetrahedron Symposium
Y2 - 28 June 2016 through 1 July 2016
ER -