Chem
Volume 6, Issue 8, 6 August 2020, Pages 2046-2059
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Article
DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaphthalene

https://doi.org/10.1016/j.chempr.2020.06.001Get rights and content
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Highlights

  • Computation-guided screening of functional groups for arene activation

  • Chemoselective C–H functionalization of 2-nitrosonaphthalene at an unconventional site

  • One-pot synthesis of optically active NOBINs by a solo organocatalytic system

  • Divergent access to two types of axially chiral arylindole frameworks

The Bigger Picture

Highly efficient conversion of inexpensive and readily available arene materials into high-value-added chiral molecules is of great importance in modern synthetic chemistry given the enormous potential of such structures in functional materials, pharmaceuticals, and other relevant chemical industries. Organocatalytic nucleophilic aromatic substitution enabled by an azo group offers an effective approach to enantioselective functionalization of naphthalene C–H bonds featuring an intramolecular oxidation of an unstabilized σH adduct. Premised on density functional theory (DFT) calculations, nitroso has emerged as another promising activating and oxidative group, whose synthetic potential is substantiated in the atroposelective synthesis of several groups of representative biaryl atropisomers processed by a chiral phosphoric acid catalyst. The success of this reaction explicitly exemplifies the ability of computational tools to streamline organic synthesis with intensified robustness in the disclosed strategy.

Summary

Functionalization of arenes represents the most efficient approach for constructing a core backbone of important aryl compounds. Compared with the well-developed electrophilic aromatic substitution and transition-metal-catalyzed C–H activation, nucleophilic aromatic substitution remains challenging because of the lack of a convenient route for rapid conversion of the σH adduct to other stable and versatile intermediates in situ. Guided by computational design, we were able to realize asymmetric nucleophilic aromatic substitution by introducing a nitroso group on naphthalene via chiral phosphoric acid catalysis. This strategy enables efficient construction of atropisomeric indole-naphthalenes and indole-anilines with excellent stereocontrol. Density functional theory (DFT) calculations provide further insights into the origins of enantioselectivity and the reaction mechanisms. The successful application in the synthesis of NOBINs (2-amino-2′-hydroxy-1,1′-binaphthyl) extends the utility of this strategy.

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Keywords

DFT calculations
chiral phosphoric acid
nucleophilic aromatic substitution
arene functionalization
axially chiral biaryls
atroposelective
nitrosonaphthalene
NOBIN

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