Enantioselective Synthesis of Axially Chiral Benzothiophene/Benzofuran‐Fused Biaryls by N‐Heterocyclic Carbene Catalyzed Arene Formation

Abstract

Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N-heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with concomitant axial chirality induction for the synthesis of biaryl atropisomers is far less developed, and the efficient synthesis of axially chiral tetra-ortho-substituted biaryls remains an unsolved problem under NHC catalysis. Reported here is an NHC-catalyzed de novo synthesis of axially chiral benzothiophene/benzofuran-fused biaryls from enals and 2-benzyl-benzothiophene/benzofuran-3-carbaldehydes through a [2+4] annulation, decarboxylation, and oxidative aromatization cascade with central-to-axial chirality conversion. The developed method provides efficient and general access to novel axially chiral benzothiophene/benzofuran-fused biaryls in high enantioselectivities and works well for the synthesis of tetra-ortho-substituted biaryls.

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

“…In the same year, an N -heterocyclic carbene ( L27 ) catalyzed [4 + 2] annulation of enals 97 with 2-benzylbenzothiophene 98 was developed for enantioselective de novo construction of ortho-substituted biaryl 99 ( Scheme 30 ) [ 95 ]. A novel axially chiral benzothiophene-fused biaryl 99 could be obtained through central-to-axial chirality conversion via a decarbonylation-aromatization cascade process.…”

N-Heterocyclic Carbene-Catalyzed Atroposelective Synthesis of N-N Axially Chiral 3-Amino Quinazolinones

“…In the last decade, a variety of structurally diverse C-C axially chiral biaryls and styrenes were demonstrated using carbene-catalyzed strategies involving kinetic resolutions, desymmetrizations, (benz)annulations, central to axial chirality transfers, etc. by the groups of Zhao, 13 Wang, 14 Lupton, 15 Zhu, 16 Du, 17 Ye, 18 and Chi (Scheme 1a). 19 Moreover, NHCs are also useful for the atroposelective synthesis of C-N axially chiral compounds.…”

Desymmetrization of N-Cbz glutarimides through N-heterocyclic carbene organocatalysis

“…In addition to aldehydes (or enals), stable and relatively less reactive esters could also be activated creatively by NHCs, which was discovered by the groups of Chi and Lupton [25][26][27][28] , significantly expanding the scope of NHC chemistry. In addition, α-activation (enolate intermediates) [29][30][31][32][33] and remote activation (such as γ [34][35][36][37] , δ 38,39 , and ε-activation 40,41 ) of the aforementioned substrates, have also been achieved significantly under NHC catalysis. Beside commonly classical twoelectron pathways, NHC-catalyzed radical reactions via a single electron transfer (SET) pathway of aldehydes or esters, and their surrogates have also received continuous attention [42][43][44][45][46] .…”