Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study
Jimmy Wang, Matthew A. Horwitz, Alexander B. Dürr, Francesco Ibba, Gabriele Pupo, Yuan Gao, Paolo F. Ricci, Kirsten E. Christensen, Tejas P. Pathak, Timothy D. W. Claridge, Guy C. Lloyd‐Jones, Robert S. Paton, Véronique Gouverneur
Abstract
-isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis.