Palladium‐Catalyzed PIDA‐Mediated δ‐C(sp³)−H Acetoxylation of Amino Acid Derivatives: Overriding Competitive Intramolecular Amination

Abstract

The selective δ‐C(sp3)−H acetoxylation of N‐(SO2Py)‐protected amino acid derivatives has been accomplished by using palladium‐catalysis and PhI(OAc)2 (PIDA) as both terminal oxidant and acetoxy source. The distinct structural and electronic features of the SO2Py compared to more traditional carbonyl‐based directing groups is essential to override the otherwise more favourable competitive intramolecular C−H amination. The δ‐site selectivity predominates over traditionally more favorable 5‐membered cyclopalladation at competitive γ‐CH2. Experimental and DFT mechanistic studies provide important insights about the mechanism and the underlying factors controlling the chemo‐ and regioselectivity.

Pd‐Catalyzed δ‐C(sp3)−H Thiolation of Amino Acid Derivatives

“…Based on our previous work on the use of N ‐SO 2 Py as DG in successfully assisted δ‐C( sp 3 )−H functionalization of AAs and peptides, [12d,14] we first explored the reactivity of the N ‐SO 2 Py‐protected α‐methyl‐leucine derivative 1 a with diphenyl disulfide, using Pd(OAc) 2 as catalyst (15 mol%), AgOAc as additive, and 1,4‐dioxane as solvent (Table 1, entry 1). Under these conditions, the δ‐thiolated product 2 a was obtained in 34% yield with a dr =3:1.…”

“…[13] Very recently, our group has achieved the N-(2-pyridyl)sulfonyl (N-SO 2 Py)-assisted δ-acetoxylation of α-AAs. [14] Therefore, new approaches capable of expanding the scope to other Cheteroatom bond forming reactions are highly appeal-ing for accessing new non-proteinogenic AAs. For this reason, continuing with our research on DG-assisted remote CÀ H bond functionalization of AAs and peptides, we decided to investigate the underdeveloped Pd-catalyzed direct δ-C(sp 3 )À H thiolation of α-AAs' side chain.…”

“…In pioneering contributions, Chen, Daugulis, Yao and Zhao, Liu and Wu explored the intramolecular amination reaction, using either the picolinamide ( N ‐COPy) as DG or an oxalyl amide auxiliary [13] . Very recently, our group has achieved the N ‐(2‐pyridyl)sulfonyl ( N ‐SO 2 Py)‐assisted δ‐acetoxylation of α‐AAs [14] . Therefore, new approaches capable of expanding the scope to other C‐heteroatom bond forming reactions are highly appealing for accessing new non‐proteinogenic AAs.…”