Base-Assisted Intramolecular C–N Coupling Reaction from NH₂-Bound Cyclopalladated l-Phenylalanine to Indoline-2-carboxylic Acid

Abstract

The deprotonative intramolecular-amination reaction of phenylalanine derived palladacycles has been investigated to highlight a facile carbonate-assisted N-H activation before the C-N bond formation. A major counter-ion effect led to divergent pathways whereby the SPhos-Pd-complex with iodine, triflate or trifluroacetate anions were key intermediates to afford an access to (S)-2-indolinecarboxylic acid derivatives. 11 3a-I DBU/toluene 100/14 -c 12 d 3a-I K2CO3/toluene 130/14 99 (61)/-c 13 d 3a-Cl K2CO3/toluene 130/14 0/46 (46) 14 d 3b-I K2CO3/toluene 130/14 63(50)/28 15 d 3b-Cl K2CO3/toluene 130/14 0/41 (38) a Reaction made with 0.1 mmol of palladacycle and 0.3 mmol of base (3 equiv) in 1 mL of solvent. b Yield determined by 1 H NMR spectroscopy with Bn2O as an internal standard. c Traces of product (< 10% by 1 H NMR). d Reaction made with 0.3 mmol of palladacycle -Isolated yields in parentheses.

Amine‐Directed Palladium‐Catalyzed C−H Halogenation of Phenylalanine Derivatives

“…Actually, this product 1 a was hardly observed in the optimized Pd-catalyzed conditions. In line with our previous observation with phenylalanine ester 1 u (giving 12 u, Scheme 2C), [23] a straightforward synthesis and isolation of the palladacycle 12 d as a solid, likely as a dimeric species, was achieved from the free-amine 1 d in the presence of Pd(TFA) 2 (likewise from 1 d•TFA and Pd(OAc) 2 ). [17,24] This protocol conveniently complement the seminal investigation of Vicente and Saura-Llama who observed the facile palladation of triflate ammonium salt of phenylalanine esters thanks to the electronpoor (and poorly coordinating) triflate anion.…”

Endogenous Group‐Directed Late‐Stage C−H Functionalization of Peptides

“…The amino group in peptides can accomplish C−H functionalization by acting as a DG. Reports have shown the effectiveness of utilizing the native amino group as an endogenous DG on amino acids [50–52] …”

“…Reports have shown the effectiveness of utilizing the native amino group as an endogenous DG on amino acids. [50][51][52] In 2019, Yuan et al developed a method to synthesize unprotected oligopeptides (3) (Scheme 1) using a late-stage palladium-catalyzed selective γ-C(sp 3 )À H arylation of 1 while keeping the configuration of all α-stereocenters intact, where the native amine group acts as a monodentate ligand. [53] A tertleucine (Tle) was inserted at the N-terminus due to its bulk and solvophobic character, which play a significant role in peptide conformation and biological activities.…”

Metal‐Catalyzed C(sp2)−H Functionalization Processes of Phenylalanine‐ and Tyrosine‐Containing Peptides

“…Very recently, Hoarau and co‐workers performed mechanistic studies on the formation of indoline compounds from the corresponding free‐amino‐bounded palladacycles [59] . Following the procedure reported by Vicente and Saura‐Llamas, [46] a series of Phe‐derived 6‐membered dimeric palladacycles ( XXXI ) were prepared.…”