Abstract
As an important platform molecule, atropisomeric QUINOL plays a crucial role in the development of chiral ligands and catalysts in asymmetric catalysis. However, efficient approaches towards QUINOL remain scarce, and the resulting high production costs greatly impede the related academic research as well as downstream industrial applications. Here we report a direct oxidative cross-coupling reaction between isoquinolines and 2-naphthols, providing a straightforward and scalable route to acquire the privileged QUINOL scaffolds in a metal-free manner. Moreover, a NHC-catalyzed kinetic resolution of QUINOL N-oxides with high selectivity factor is established to access two types of promising axially chiral Lewis base catalysts in optically pure forms. The utility of this methodology is further illustrated by facile transformations of the products into QUINAP, an iconic ligand in asymmetric catalysis.
Highlights
As an important platform molecule, atropisomeric QUINOL plays a crucial role in the development of chiral ligands and catalysts in asymmetric catalysis
A streamlined access to a core framework from which modular installation of diversity is feasible for divergent construction of functional molecules, will greatly accelerate the development of these fields. 1-(Isoquinolin-1-yl)naphthalen-2-ol (QUINOL), a representative atropisomeric heterobiaryl, was described to function as reliable N–O chelating ligand in the controlled polymerization of cyclic esters[8] while itself has been synthesized as a platform molecule to access other iconic ligands such as QUINAP9–13, QUINOX14,15 and IAN16,17
The N-acyl activation mode in Reissert reaction has been demonstrated to be one of the most efficient protocols for direct C–H functionalization of six-membered heteroarenes by Fier[25,26] and McNally’s group[27,28,29,30]. Building on these literature precedents, we envisaged the suitability of this activation mode to direct selective arylation of isoquinoline with 2-naphthol which will occur through a sequence of nucleophilic addition and oxidative re-aromatization to construct QUINOLs (Fig. 1c)
Summary
As an important platform molecule, atropisomeric QUINOL plays a crucial role in the development of chiral ligands and catalysts in asymmetric catalysis. A NHC-catalyzed kinetic resolution of QUINOL N-oxides with high selectivity factor is established to access two types of promising axially chiral Lewis base catalysts in optically pure forms. The utility of this methodology is further illustrated by facile transformations of the products into QUINAP, an iconic ligand in asymmetric catalysis. The venerable Suzuki–Miyaura coupling reaction in the transition metal catalysis domain provides a reliable entry[19,20] but the necessity to pre-functionalize the coupling partners has elongated step counts, hampering overall efficiency which culminates in the high production costs (Fig. 1b) This is reflected in the prices of some commercially available ligands derived from QUINOL. Scalable synthesis and useful transformation have demonstrated the utility of this methodology
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