We report the development of a multicatalytic, one-pot, asymmetric Michael/Stetter reaction between salicylaldehydes and electrondeficient alkynes. The cascade proceeds via amine-mediated Michael addition followed by an N-heterocyclic carbene-promoted intramolecular Stetter reaction. A variety of salicylaldehydes, doubly activated alkynes, and terminal, electrophilic allenes participate in a one-step or two-step protocol to give a variety of benzofuranone products in moderate to good yields and good to excellent enantioselectivities. The origin of enantioselectivity in the reaction is also explored; E∕Z geometry of the reaction intermediate as well as the presence of catalytic amounts of catechol additive are found to influence reaction enantioselectivity.catalysis | organic synthesis | tandem catalysis
Asymmetric hydroheteroarylation of
alkenes represents a convenient
entry to elaborated heterocyclic motifs. While chiral acids are known
to mediate asymmetric addition of electron-rich heteroarenes to Michael
acceptors, very few methods exploit transition metals to catalyze
alkylation of heterocycles with olefins via a C–H activation,
migratory insertion sequence. Herein, we describe the development
of an asymmetric, intermolecular hydroheteroarylation reaction of
α-substituted acrylates with benzoxazoles. The reaction provides
2-substitued benzoxazoles in moderate to excellent yields and good
to excellent enantioselectivities. Notably, a series of mechanistic
studies appears to contradict a pathway involving enantioselective
protonation of a Rh(I)–enolate, despite the fact that such
a mechanism is invoked almost unanimously in the related addition
of aryl boronic acids to methacrylate derivatives. Evidence suggests
instead that migratory insertion or beta-hydride elimination is enantiodetermining
and that isomerization of a Rh(I)–enolate to a Rh(I)–heterobenzyl
species insulates the resultant α-stereocenter from epimerization.
A bulky ligand, CTH-(R)-Xylyl-P-Phos, is crucial
for reactivity and enantioselectivity, as it likely discourages undesired
ligation of benzoxazole substrates or intermediates to on- or off-cycle
rhodium complexes and attenuates coordination-promoted product epimerization.
Cause and effect: In science, language is often subordinated to empirical data, but words can influence our ability to understand and communicate science. This Essay argues that imprecise language has confounded studies that probe the interactions underlying the anomeric effect and related phenomena.
Anomerer Effekt ·Sprache ·Umgekehrter anomerer Effekt ·W issenschaftliche Methode ·W issenschaftsphilosophie InderWissenschaftistesleicht,dieSprachedenempirischen Daten unterzuordnen. Doch die Worte,mit denen wir unsere Beobachtungen und Schlussfolgerungen beschreiben, kçnnen unsere Art und Weise,d ie Welt zu begreifen, beeinflussen. Dieser Essay bietet zwei kritische Analysen von Studien des anomeren Effekts,die deutlich machen, wie sich Genauigkeit in der Sprache auf die Qualität unserer Wissenschaft auswirken kann. Die erste Fallstudie legt dar,d ass die lange bestehende Terminologie,die zwischen Ursache und Wirkung kaum unterscheidet, zu einer viel beachteten Diskussion über die Ursache von spektroskopischen Verschiebungen in einem Zucker-Peptid-Komplex beiträgt (J. Am. Chem. Soc. 2011, 133,13731 vs. Nature 2011, 469,76). In der zweiten Fallstudie fçrdern unvollständige Definitionen die Ablehnung einer direkten Hypothese zum konformativen Verhalten bestimmter heterocyclischer Systeme zugunsten einer zweifelhaften Hypothese:d er umgekehrte anomere Effekt. Die Erkenntnisse,d ie durch Untersuchung dieser Fälle gewonnen wurden, sollen Wissenschaftler in allen Fachgebieten davon überzeugen, nicht nur die Durchführung ihrer Forschungen, sondern auch deren Vermittlung mit Sorgfalt zu handhaben.
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