Catalytic Asymmetric Allylic Alkylation with Arylfluoroacetonitriles

Abstract

A palladium(phosphinoxazoline) catalyzed method for asymmetric allylic alkylation of α-aryl-α-fluoroacetonitriles is introduced. This reaction achieves C−C bond formation and incorporation of two adjacent chirality centers with moderate to good yields, high enantioselectivities, and up to 15:1 dr.

The Catalytic Asymmetric Allylic Alkylation of Acyclic Enolates for the Construction of Quaternary and Tetrasubstituted Stereogenic Centres

“…More recently, Wolf described the palladium‐catalysed AAA reaction of arylfluoroacetonitriles 26 (Scheme 4). [12] Using substituted allylic electrophiles 27 , DBU as the base and chiral ligand ( S )‐ L2 for palladium, a library of allylated products 28 a – c bearing two contiguous stereogenic centres could be accessed with moderate to high diastereoselectivity and excellent enantioselectivity (4 : 1 to >15 : 1 dr and ≥99 % ee). Mechanistically, α‐deprotonation of nitrile 26 gives prochiral nucleophilic intermediate 29 that then undergoes allylation with a π‐allylpalladium(II) intermediate.…”

Recent advances in stereoselective construction of fluorinated quaternary carbon centers from fluorinated compounds

“…In 2022, Wolf's group developed an asymmetric allylic alkylation with arylfluoroacetonitriles catalyzed by a palladium ( phosphinoxazoline) catalyst, which can achieve the formation of C-C bonds and the combination of two adjacent chiral centers (Scheme 38). 45 In this method, compounds containing two contiguous chiral centers and fluorine were synthesized with moderate yields of 60-78%, in up to 15 : 1 dr and >99% ee by the use of a palladium chiral catalyst and DBU as a base. The authors went further and performed the Stille cross-coupling reaction, contributing to the synthetic application of this class of α-aryl-α-fluoroacetonitrile compounds.…”

Enantioseparation and racemization of 3‐fluorooxindoles

“…To this end, we recently investigated the racemization kinetics of 2-aryl-2-fluoroacetonitriles and developed catalytic asymmetric allylic alkylation and stereodivergent Mannich reactions with this emerging class of compounds. [10][11][12] Following our continuous interest in chiral organofluorines, [13][14][15][16][17][18][19][20][21][22][23][24] we now wish to disclose the results of a racemization study with 3-fluorooxindoles, which are frequently employed in catalytic asymmetric reaction developments and represent an important pharmacophore encountered in the potassium channel modulator Maxipost and other biologically active compounds. 25,26 Semipreparative chiral HPLC enantioseparation of the oxindoles 1-5 shown in Figure 1 using a Whelk-O 1 or Chiralpak IB column produced highly enantioenriched samples that were subjected to catalytic or stoichiometric base amounts at room temperature.…”

“…The stereochemical integrity of organofluorines, however, is poorly understood, and few studies that quantify the propensity to racemization and the role of fluorine when positioned at an enolizable chiral carbon center have been reported. To this end, we recently investigated the racemization kinetics of 2‐aryl‐2‐fluoroacetonitriles and developed catalytic asymmetric allylic alkylation and stereodivergent Mannich reactions with this emerging class of compounds 10–12 . Following our continuous interest in chiral organofluorines, 13–24 we now wish to disclose the results of a racemization study with 3‐fluorooxindoles, which are frequently employed in catalytic asymmetric reaction developments and represent an important pharmacophore encountered in the potassium channel modulator Maxipost and other biologically active compounds 25,26 …”