Organocatalytic Asymmetric Annulation of ortho‐Alkynylanilines: Synthesis of Axially Chiral Naphthyl‐C2‐indoles

Abstract

A chiral Brønsted base catalyzed asymmetric annulation of ortho‐alkynylanilines has been developed to access axially chiral naphthyl‐C2‐indoles via vinylidene ortho‐quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl‐C2‐indole skeletons with excellent enantioselectivity and functional‐group tolerance. This transformation was applicable to decagram‐scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl‐C2‐indoles for a series of carbon–heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl‐C2‐indoles were applied as a chiral skeleton for organocatalytic aza‐Baylis–Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.

Rhodium‐Catalyzed Atroposelective Construction of Indoles via C−H Bond Activation

“…Nevertheless, these very few reports [12–14] are limited to 6,6‐biaryl synthesis due to reactivity challenge posed by employment of bulky directing group and/or coupling reagent. The rarity of axially chiral indoles via C−H activation [9] is partially ascribed to the relatively low atropostability associated with pentatomic biarlys [2g,h, 9, 11l] . Notably, Rh III ‐catalyzed C−H activation has allowed facile access to a large array of chiral products [9, 12–15] .…”

Catalytic Asymmetric Construction of Axially Chiral Indole‐Based Frameworks: An Emerging Area

“…Recently, the Yan group devised an innovative strategy for constructing axially chiral C2‐naphthylindoles 48 via asymmetric catalysis based on their understanding of vinylidene ortho ‐quinone methide (VQM) chemistry [33] . As illustrated in Scheme 13 a, they proposed that ortho ‐alkynylanilines 47 could transform into chiral VQM intermediates in the presence of the chiral Brønsted base C12 , and these intermediates subsequently underwent an intramolecular cyclization to generate an indole ring and C2‐arylindole axis [34] . Notably, this strategy could be utilized for the decagram‐scale synthesis of C2‐naphthylindole 48 a in an excellent yield with perfect enantioselectivity (Scheme 13 b).…”

Organocatalytic Asymmetric Methodologies towards the Synthesis of Atropisomeric N-Heterocycles

“…These heterocycles display exquisite configurational stability of the C-2 naphthalene axis, as long as bulky groups, such as t Bu or Ts, are present at N-1 (Scheme 10). 33 The reaction proceeds through the intermediacy of vinylidenequinone methides 45, generated by prototropic rearrangement of the substrates, induced by catalyst M. The aforementioned allene-intermediates 45 display axial chirality, undergoing an axial (allene) to axial (arene-arene) chirality transfer to give the final products 43. These were obtained in very high yields and selectivities and were shown to be amenable to a myriad of transformations, taking advantage of the nucleophilic C-3 position.…”