Highly Enantioselective α‐Cyanation with 4‐Acetylphenyl Cyanate

Abstract

A highly effective asymmetric version of α-cyanation of β-keto esters and amides was developed with a Lewis-acid catalyst. Thus, by using 10 mol % of a tridentate bisoxazoline-zinc(II) complex as the catalyst, a series of chiral nitriles containing a quaternary carbon center were obtained in excellent enantioselectivities (up to 97 % enantiomeric excess) and up to 95 % yield in the presence of 4 Å molar sieve at room temperature. For the first time, mild and active 4-acetylphenyl cyanate was used instead of cyano-hyperiodinate as the cationic cyano source for catalytic asymmetric α-cyanation.

Recent developments in enantioselective zinc-catalyzed transformations

“…To explain the stereochemical outcome of the reaction, the authors proposed the catalytic cycle depicted in Scheme 83. After formation of the initial dinuclear zinc catalyst, Scheme 84. a-Cyanations of b-ketoesters and b-ketoamides with p-acetylphenylcyanate in the presence of a bisoxazoline ligand [119].…”

“…Along with a-aminations, asymmetric a-cyanations of bketocarbonyl compounds have been developed in the presence of chiral zinc catalysts. For example, Chen et al reported a novel methodology for enantioselective a-cyanation of b-ketoesters which was based for the first time on the use of p-acetylphenyl cyanate 247 as cationic cyano source [119]. As illustrated in Scheme 84, the reaction of the latter with a series of b-ketoesters 248 performed at room temperature in dichloromethane as solvent in the presence of a chiral zinc catalyst in situ generated from 10 mol% of Zn(BF 4 ) 2 (H 2 O) 6 and 12 mol% of bisoxazoline ligand (S, S)-249 yielded the corresponding chiral a-nitriles 250 in both moderate to high yields (30-95%) and enantioselectivities (47-97% ee).…”

Recent Advances in the Synthesis of β-Ketonitriles

“…As shown in Scheme 24, the bisoxazoline-based zinc complex prepared from Zn(II) salts with the tridentate dibenzofuran bisoxazoline 12 was found to be effective for the enantioselective cyanation of β-keto esters and amides with readily available 4-acetylphenyl cyanate, which has good solubility and mild reactivity. 42 The presence of an acetyl group at the 4-position of the cyanate is essential for achieving a high degree of enantioselectivity. When 10-20 mol% of the catalysts in CH 2 Cl 2 are used in the reaction at room temperature, both five-and six-membered esters and amides were converted into the corresponding products in excellent yields and with up to 97% ee, while the cyanation of a seven-membered ester resulted in a low enantioselectivity.…”

Enantioselective Copper-Catalyzed Electrophilic Dearomative Azidation of β-Naphthols

“…Flexible tridentate bisoxazoline ligand L3 resulted in slightly higher enantioselectivity (47%, entry 3). The combination of Cu­(OTf) 2 with dbfox ligands ( L4 – L7 , dbfox = 4,6-dibenzofurandiyl-2,2′-bisoxazoline) was found to provide very promising results (entries 4–7), and Cu­(OTf) 2 / L4 enabled the preparation of 3a in 86% yield with 66% ee (entry 4).…”