Base-Catalyzed Asymmetric α-Functionalization of 2-(Cyanomethyl)azaarene N-Oxides Leading to Quaternary Stereocenters

Abstract

A simple, new strategy for the direct asymmetric α-functionalization of 2-alkyl azaarenes is described. Specifically, a Brønsted base catalyzed conjugate addition of substituted 2-cyanomethylpyridine (and pyrazine) N-oxides to acrylate equivalents to afford hitherto elusive 2-tert-alkyl azaaryl adducts with high enantioselectivity (up to 94% ee) is realized. Extension of the method to the α-amination reaction by using azodicarboxylate esters as electrophiles is also demonstrated. Key for success is the N-oxide functionality of substrates that acts as a removable activating and stereodirecting group. A bifunctional Brønsted base catalyst bearing a squaramide with an attached bulky silyl group is also disclosed.

Enantioselective Synthesis of Alkyl Azaarenes

“…One example of asymmetric CH functionalization, is reported by Palomo et al, using differently substituted 2cyanomethyl pyridine and pyrazines N-oxides. [2] Compounds 9 were reacted with enone 10 as acrylate equivalent to obtain ortho-substituted azaarenes (Scheme 3, top). The best catalyst was found to be a bifunctional squaramide-Bronsted base with a bulky silyl group (I, II).…”

“…The best reaction conditions involve the use of (S,S)-Ph-BOX (12 mol%), Ni(acac) 2 (10 mol%) in iPrOH at 0°C under nitrogen. The catalytic system is generated from Ni(acac) 2 and BOX ligand 43. The nitro and the trifluoromethyl groups are fundamental for achieving good results in terms of yield and enantioselectivity.…”

Strategy for Stereoselective Metal‐free α‐Functionalization of 2‐Azaaryl Acetates with N‐Boc Imines

“…To date, only a few methods to control reactivity and stereoselectivity in reactions involving 2‐alkyl azaarenes for example, 2‐alkyl pyridines and quinolines have been accomplished through different approaches . Recently, we have reported the enantioselective α‐functionalization of (cyanomethyl)azaarene N ‐oxides to generate quaternary stereogenic centers with high enantioselectivity . In this approach, the N ‐oxide functionality plays a dual role.…”

“…[7] Recently, we haver eported the enantioselective a-functionalization of (cyanomethyl)azaarene N-oxides to generate quaternary stereogenicc enters with high enantioselectivity. [8] In this approach, the N-oxide functionality plays ad ual role. On the one hand,i tf acilitates deprotonation at the exocyclic azaarene acarbons ide chain, and on the otherh and, it acts as ap owerful temporary stereodirecting group.…”

Highly Enantioselective Synthesis of Alkylpyridine Derivatives through a Michael/Michael/Aldol Cascade Reaction

“…However, upon applying this synergistic approach to 2‐methylpyridine derivatives, very low yields were obtained. Notably, in all the previous examples one of the limitations was the generation of quaternary α‐stereocenters, as only tertiary stereocenters were synthesized …”