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

Abstract

Although the atroposelective synthesis of biaryls and related compounds bearing axially chiral C-C bonds are well-known, the synthesis of axially chiral C-N bond-containing compounds are relatively less explored, and the construction of axially chiral N-N bonds has received only scant attention. Demonstrated herein is the N-heterocyclic carbene (NHC)-catalyzed selective amidation reaction leading to the atroposelective synthesis of N-N axially chiral 3-amino quinazolinones. The NHC-catalyzed reaction of quinazolinones containing a free N-H moiety with -unsaturated aldehydes under oxidative conditions furnished the atropisomeric quinazolinone derivatives under mild conditions and broad scope. Preliminary studies on experimental and DFT-based N-N rotational barrier determination is also presented.

Atroposelective synthesis of N–N axially chiral pyrrolyl(aza)-quinolinone by de novo ring formation

“…14 Very recently, an N-heterocyclic carbene-catalyzed amidation reaction for the atroposelective synthesis of N-N axially chiral 3-amino quinazolinones was demonstrated by the Biju group. 15 Liu and Lu synthesized 1,1′-bipyrrole atropisomers through the desymmetrization strategy via asymmetric Cu-catalyzed alkylation and arylation reactions. 16 More recently, the Liu group realized Pd-catalyzed transient directing groupenabled atroposelective C-H functionalizations such as alkenylation, alkynylation, allylation, and arylation reactions of pyrroles or indoles for an efficient synthesis of indole-pyrrole atropisomers.…”

Atroposelective Synthesis of N–N Axially Chiral Indoles and Pyrroles via NHC-Catalyzed Diastereoselective (3 + 3) Annulation Strategy

“…Very recently, our group disclosed the NHCcatalyzed route for synthesizing N−N axially chiral 3-amino quinazolinone derivatives via the atroposelective amidation strategy (Scheme 1b). 20 Encouraged by this result, we envisioned an approach for the superposition of point chirality and N−N axis to enhance the topological diversity in three-dimensional space, thereby expanding their range of potential applications. 21 However, such a strategy could face notable difficulties, particularly in achieving concurrent generation of axial chirality and point chirality in a single step and in regulating diastereoselectivity and enantioselectivity throughout the creation of multiple chiral components.…”

Catalytic N-Acylation for Access to N–N Atropisomeric N-Aminoindoles: Choice of Acylation Reagents and Mechanistic Insights

“…For example, quinidine and phasetransfer catalysis achieved N-alkylation. 11,21 NHC 22 and chiral isothiourea 23 catalysts achieved N-acylation, in which chained anhydrides or chained aldehydes are used as acylation reagents (Figure 1b). Despite these advancements in obtaining chiral N− N axes, there remains an urgent need to develop potent enantioselective tools for the rapid and efficient synthesis of axially chiral N−N compounds.…”