Asymmetric synthesis of chromans via the Friedel–Crafts alkylation–hemiketalization catalysed by an N,N′-dioxide scandium(iii) complex

Abstract

The direct and sequential Friedel–Crafts alkylation/hemiketalization procedures for the synthesis of chiral chromans resulted in excellent yields, high enantioselectivities and high diastereoselectivities for a broad range of substrates.

Diastereoselective construction of 4-indole substituted chromans bearing a ketal motif through a three-component Friedel–Crafts alkylation/ketalization sequence

“…On the basis of the experimental results and previous reports, 8,10,11 g , h a possible reaction mechanism was proposed to explain the reaction pathway and the stereochemistry ( Scheme 6 , taking the formation of 3a as an example). First, a Friedel–Crafts alkylation between N -benzyl indole 1a and ortho -hydroxychalcone 2a took place to deliver the intermediate A.…”

“… 3 Given the medicinal relevance and the intriguing scaffolds of chroman and indole, integration of them into one complex molecule would contribute greatly to medicinal chemistry, which not only inherit the structures and properties of both biologically active skeletons, but may grant a few new bioactivities. However, only limited methods were available for the synthesis of indole-substituted chromans and the developed approaches mainly involved cycloaddition of 2-vinyl-1 H -indole with 3-nitro-2 H -chromenes, 4 substitution, 5 domino Knoevenagel-hetero-Diels–Alder reactions, 6 Friedel–Crafts alkylation of indoles with 3-nitro-2 H -chromenes, 7 Friedel–Crafts alkylation-inspired cyclizations, 8 and others. 9 Despite these elegant works, many of these methodologies suffer from limitations of substrate availability, synthetic efficiency and product diversity, which may limit their applicability in synthetic chemistry.…”

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…Subsequently, Liu and Feng et al. expanded the [3 + 3] annulation of β,γ -unsaturated α -ketoesters to electron-rich phenols, using their developed N , N ′-dioxide scandium (III) catalytic system ( scheme 15 B) ( Hao et al., 2017 ). Excellent yields (71–97%) and high enantioselectivities with high diastereoselectivities (80–95% ee, 6:1 to 14:1 dr) were achieved under mild conditions.…”

Intramolecular Oxidative Coupling between Unactivated Aliphatic C–H and Aryl C–H Bonds

“…Chromane and tetralin are vital structural units in natural products and pharmaceutical molecules (Scheme a) . In general, chromanes are synthesized through the reduction of chromanones, intramolecular C–O formations, cross-coupling of organohalides with different partners, as well as Friedel–Crafts alkylations, while tetralins are constructed through hydrogenation of naphthalenes, Friedel–Crafts cyclization of aryl derivatives, or C–H alkylation of alkene tethered arenes . Apparently, the direct oxidative coupling between aliphatic and aromatic C–H bonds via transition-metal catalysis would be a straightforward, atomic- and step-economic method to construct such benzo-fused cyclic structural units from linear starting materials equipped with phenyl substituents, providing an efficient strategy to approach the fused ring systems.…”