Sulfonamide‐Promoted Palladium(II)‐Catalyzed Alkylation of Unactivated Methylene C(sp³)H Bonds with Alkyl Iodides

Abstract

The alkylation of unactivated β-methylene C(sp(3))-H bonds of α-amino acid substrates with a broad range of alkyl iodides using Pd(OAc)2 as the catalyst is described. The addition of NaOCN and 4-Cl-C6H4SO2NH2 was found to be crucial for the success of this transformation. The reaction is compatible with a diverse array of functional groups and proceeds with high diastereoselectivity. Furthermore, various β,β-hetero-dialkyl- and β-alkyl-β-aryl-α-amino acids were prepared by sequential C(sp(3))-H functionalization of an alanine-derived substrate, thus providing a versatile strategy for the stereoselective synthesis of unnatural β-disubstituted α-amino acids.

Palladium-Catalyzed Transformations of Alkyl C–H Bonds

“…127 In the latter case, the alkyl halide partners are limited to methyl iodide and α-haloacetates. To broaden the scope with respect to the coupling partners, 128,129 Shi group developed a robust catalytic system using NaOCN and 4-chlorobenzenesulfonamide as effective additives. 128 The alkylation of α-amino acid substrates 125 is tolerant of various alkyl halides, and proceeds with high levels of diastereoselectivity.…”

Divergent and Stereoselective Synthesis of β‐Silyl‐α‐Amino Acids through Palladium‐Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C−H Bonds

“…Synthesis of the Palladacycle Int-B [6] Pd(OAc) 2 (224.5 mg, 1.0 mmol) and 2a (421.5 mg, 1.0 mmol) were added to CH 3 CN/DCE (12 mL+6 mL). The reaction was stirred at 50 o C for 4 h, and then the solvent was removed under vacuum.…”

Diastereoselective Substrate-Controlled Transition-Metal-Catalyzed C–H Activation: An Old Solution to a Modern Synthetic Challenge

“…32 A further major advance in such diastereoselective alkylation was disclosed by Chen and Shi in 2014. 36 An intensive optimization study revealed that nonactivated alkyl halides could also be efficiently coupled with the amino acid derivatives when a sulfonamide ligand (4-chlorobenzenesulfonamide) and sodium cyanate base were added to the reaction mixture. The particular efficiency of this sulfonamide ligand can be attributed to its labile character.…”