A Multicomponent Reaction of Amies, Isocyanides, and Terminal Alkynes: Highly Chemo- and Regioselective Synthesis of Polysubsti-tuted Pyridines and Isoquinolines

摘要

Pyridine, a class of important heterocycles, is not only the fundamental motif found in the core of numerous alkaloids but is also a pivotal building block for pharmaceutical compounds and chiral ligands. Although many methods have been developed for their synthesis, lengthy or complicated procedures as well as harsh reaction conditions are usually applied. Thus, it is still important to develop direct and efficient routes that afford pyridine derivatives under mild conditions. Arynes are an important intermediate in organic synthesis and have received attention over the past decades. Because of their low-lying LUMO, arynes exhibit highly electrophilic character; even neutral nucleophiles can easily add to arynes to produce zwitterions, which act as key intermediates in the subsequent transformation that can lead to a variety of benzoannulated compounds. This feature has been successfully explored by Yoshida et al. in the three-component reaction of arynes, isocyanides, and aldehydes, ketones, or imines for the direct synthesis of benzoannulated iminofurans and 2-iminoisoindolines. However, examples of multicomponent reactions (MCR) containing both arynes and isocyanides are still limited owing to the obvious difficulty in regulating the reactivity of the aryne component ; especially the control of chemo- and regioselectivity remain challenging. We envisioned that an adduct of benzyne and isocyanide (generated in situ) may be trapped by a terminal alkyne to form a reactive imide intermediate A, which may further undergo a 1,5-hydride shift to produce an allenyl inline intermediate B (Scheme l). Then a consecutive cycloaddition reaction of B with another molecule of benzyne or terminal alkyne may occur to afford useful heterocyclic compounds. Herein we reported our results on this novel multicomponent reaction, which provides a direct and mild synthesis of polysubstituted pyridines and isoquinolines with high chemo- and regioselectivity. An attractive feature of this protocol is that four molecules could be directly assembled into the desired azacyclic compounds in a highly efficient and atom-economic manner.