Squaramide‐Catalyzed Asymmetric aza‐Friedel–Crafts/N,O‐Acetalization Domino Reactions Between 2‐Naphthols and Pyrazolinone Ketimines

Abstract

N-Boc ketimines derived from pyrazolin-5-ones were explored to develop an unprecedented domino aza-Friedel-Crafts/N,O-acetalization reaction with 2-naphthols. The novel method requires a catalyst loading of only 0.5 mol % of a bifunctional squaramide catalyst, is scalable to gram amounts, and provides a new series of furanonaphthopyrazolidinone derivatives bearing two vicinal tetra-substituted stereogenic centers in excellent yields (95-98 %) and stereoselectivity (>99:1 d.r. and 97-98 % ee). A different reactivity was observed in the case of 1-naphthols and other electron-rich phenols, which led to the aza-Friedel-Crafts adducts in 70-98 % yield and 47-98 % ee.

Organocatalytic Enantioselective aza‐Friedel‐Crafts Reactions of Pyrazolinone Ketimines with Hydroxyindoles and Electron‐Rich Phenols

“…Very recently, Enders’ group explored a new class of ketimines derived from pyrazolin‐5‐ones to convert its C4‐nucleophilic reactivity to electrophilic and developed several enantioselective transformations . Among them, the organocatalytic asymmetric aza‐Friedel‐Crafts/N,O‐acetalization domino reactions between 2‐naphthols and pyrazolinone ketimines were reported, while only the aza‐Friedel‐Crafts reactions were occurred in the case of 1‐naphthols and electron‐rich phenols . We envisioned that pyrazolinone ketimines serve as electrophiles to realize the enantioselective functionalization on benzene ring of indoles (Figure ).…”

“…Subsequently, the potential of this aza‐Friedel‐Crafts reaction with electron‐rich phenols was further evaluated (Scheme ). Notably, up to date, methods of enantioselective addition of sesamol to ketimines are scarce ,. Gratifyingly, with sesamol 8 and 2,3‐dimethoxyphenolm 10 , the corresponding pyrazolone derivatives 9 and 11 were formed with 99% and 98% ee, respectively, while only moderate results ( 9 , 47% ee and 11 , 53% ee) were reported by Enders’ group .…”

“…Notably, up to date, methods of enantioselective addition of sesamol to ketimines are scarce ,. Gratifyingly, with sesamol 8 and 2,3‐dimethoxyphenolm 10 , the corresponding pyrazolone derivatives 9 and 11 were formed with 99% and 98% ee, respectively, while only moderate results ( 9 , 47% ee and 11 , 53% ee) were reported by Enders’ group . Additionally, 3‐(dimethylamino)phenol 12 was also well tolerated, affording the desired product 13 in 85% yield and 99% ee.…”

Organocatalyzed Enantioselective Decarboxylative Mannich Reaction of β‐Ketoacids with Pyrazolinone Ketimines for the Construction of Chiral β‐Amino Ketone‐Pyrazolinone Derivatives

“…In 2017, Enders' group described the first organocatalytic enantioselective Strecker reaction of pyrazolone derived ketimine electrophiles for the synthesis of pyrazolone α‐aminonitrile derivatives (Scheme a) . Later, chiral squaramide‐catalyzed asymmetric aza‐Friedel–Crafts/N,O acetalization domino reactions between 2‐naphthols and pyrazolinone ketimines, and asymmetric Mannich reaction of pyrazolones and pyrazolinone ketimines were reported by Enders' group, respectively (Scheme b and 1c). In 2018, Deng's group reported organocatalytic asymmetric aza‐Friedel‐Crafts reaction of pyrazolinone ketimines with hydroxyindoles to access chiral indole‐pyrazolinone derivatives (Scheme d) .…”

Direct Asymmetric Arylation of Imines

“…A squaramide-catalyzed asymmetric domino addition/N,O-acetalization reaction between 2-naphthols and N-Boc ketimines of pyrazolinones was developed (Scheme 69). [83] It provided furanonaphthopyrazolidinone derivatives bearing two vicinal tetrasubstituted stereogenic centers in excellent yields and stereoselectivity. A different reaction pathway was observed in the case of 1-naphthols or electron-rich phenols, which allowed direct access to amino-pyrazolone derivatives through an aza-Friedel-Crafts reaction.…”