Toward a Catalytic Atroposelective Synthesis of Diaryl Ethers Through C(sp2)–H Alkylation with Nitroalkanes

Abstract

Herein we report studies towards a small molecule catalytic approach to access atropisomeric diaryl ethers that proceeds via a C(sp2)-H alkylation using nitroalkanes as the alkyl source. A quaternary ammonium salt derived from quinine containing a sterically hindered urea at the C-9 position was found to effect atroposelective C(sp2)-H alkylation with moderate to good enantioselectivities across several naphthoquinone-containing diaryl ethers. Products can then be isolated in greater than 95:5 er after one round of trituration. For several substrates that were evaluated we observed a ‘nitroethylated’ product in similar yields and selectivities.

Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution

“…Solvent screening revealed that the reaction went smoothly in various solvents, but 1,4-dioxane was the best choice (entries [8][9][10][11][12]. Evaluation of the bases showed that weak organic and inorganic bases did not work for this reaction, while DBU and K 2 CO 3 led to much better enantioselectivity with slightly reduced yields (entries [13][14][15][16]. Improvement of the yield with excellent enantioselectivity was achieved for the reaction with 15 mol % loading of preNHC E (entries 17 vs [18][19].…”

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…In 2018, Gustafson and colleagues published an atroposelective synthesis of diaryl ethers via C­(sp 2 )–H methylation with nitromethanes, utilizing quinine-derived quaternary ammonium cations as catalysts (Figure ). The methylation reaction was optimized using substrate 51.1 , along with 10 equiv of NO 2 Me, 10 equiv of K 3 PO 4 , 10 mol % of catalyst 51.2 , and 3 Å molecular sieves (MS) in toluene at room temperature for 24 h, leading to the formation of product 51.3 in 68% yield and 82:18 er, along with a nitroethylated side product 51.4 . The substrate scope was evaluated; however, lower yields and enantioselectivities were observed for substitutions at the ortho position of the phenyl ring other than chloride ( 51.5 – 51.7 ).…”

Enantioselective Synthesis of “NO2···NH” Hydrogen Bond-Stabilized C–N Axially Chiral Diarylamines

“…Atropisomerism, a form of conformational chirality resulting from hindered rotation about a σ-bond, has been observed in various pharmaceutically relevant scaffolds . Known rotation-restricted σ-bonds in atropisomers include C–X bonds (X = C, N, O, P, S, B) and X–X (X = N) bonds . Acyclic diaryl secondary amines, possessing two potential contiguous atropisomeric C–N axes, represent one of the most privileged scaffolds in biologically active natural products and pharmaceuticals (Scheme a).…”