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Pd-Catalyzed One-Pot Borylation/Intramolecular Asymmetric Arylation on α-Ketiminoamides: Innovative Approach to Chiral 3-Amino-2-oxindoles
Abstract
3-Amino-2-oxindole derivatives are a common framework found in many natural products and medicinal compounds and thus their synthesis is of significant importance. We report for the first time a one-pot approach for the synthesis of these compounds, using a borylation/intramolecular asymmetric arylation sequence starting from ortho -bromo-α-ketimino amide derivatives. Pd(OAc) 2 was used as the pre-catalyst along with ( R )-BINAP as the chiral source. We successfully obtained a family of 3-phenyl-3-(aryl-amino)-indolin-2-one derivatives (11 in total) with excellent yields (up to 98%) and enantioselectivities of up to 76% ee. The reaction is versatile and tolerant of a wide range of functional groups.
Transition metal‐catalyzed borylation has emerged as a powerful and versatile strategy for synthesizing organoboron compounds. These compounds have found widespread applications in various aspects, including organic synthesis, materials science, and medicinal chemistry. This review provides a concise summary of the recent advances in palladium‐ and rhodium‐catalyzed borylation from 2013 to 2023. The review covers the representative examples of catalysts, substrates scope and reaction conditions, with particular emphasis on the development of catalyst systems, such as phosphine ligands, NHC‐carbene, and more. The diverse array of borylative products obtained for further applications in Suzuki‐Miyaura coupling, and other transformations, are also discussed. Future directions in this rapidly evolving field, with the goal of designing more efficient, selective borylation methodologies are highlighted, too.
In the last decade, our group has been very active at developing and assaying complex libraries of scaffolds with a focus on their potential to identify bioactive drug candidates for neurodegenerative diseases, particularly Alzheimer’s disease (AD). Attention has been focused on isatin-based oxindole scaffolds, for which promising results concerning butyrylcholinesterase (BuChE) inhibitory activity have previously been obtained. Considering some published reports and detailed analysis of the pharmacophores of commercially available drugs for AD (powerful cholinesterase (ChE) inhibitors), we performed a strategic structural modification of the isatin core and generated a new family of isatin-based oxindole hybrids (27 new compounds) possessing crucial key functional units in their framework. The syntheses were accomplished using multiple approaches, including simple N-alkylation reactions, copper-catalyzed amination reactions, and click chemistry. The resulting library was evaluated on ChE and MAO enzymes, both of which are involved in the pathophysiology of neurodegeneration. IC50 values of 1.6 and 2.6 μM (BuChE assays), were achieved for the best inhibitors.
A one‐step, three‐component Petasis reaction of isatin derived 5‐arylboronate‐3‐substituted oxindole derivatives with salicylaldehydes and secondary amines affords new enantiomerically pure structurally diverse 5‐α‐(3‐substituted‐oxindole)‐benzylamine derivatives. The reaction shows good substrate and reagent scope affording the products with good to excellent yields (up to >99 % yield) and enantioselectivities (up to 99 % ee) using cheap and readily available (R)‐BINOL as the organocatalyst. A diastereoselective version of the reaction was also developed where moderate yields (37 to 55 % yield), excellent enantioselectivities (up to 99 % ee) and good diastereoselectivities (up to 86 % de) were obtained for new 5‐α‐(3‐hydroxy‐oxindole)‐benzylamine derivatives, having two stereocenters. The reaction is also feasible on gram‐scale.
Unprecedented α-imino N-acyl pyrazoles were efficiently and selectively prepared through the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed reaction of nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol reaction/dehydration sequence. The α-imino acyl pyrazoles were demonstrated to be new versatile intermediates for practical one-pot syntheses of α-imino amides, dipeptide precursors, esters, and β-amino alcohols. The synthetic method competes with known protocols in terms of ready availability of the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the α-imino acid derivatives achievable.
Many benzofused cyclic chiral alcohols are biologically active and a variety of synthetic methods has been developed to access these structures. Palladium‐catalyzed intramolecular nucleophilic addition reactions of aryl boron and aryl halide compounds to carbonyls are useful, but control over the cyclization to give a single product has to‐date proven challenging. Here, we describe the first controlled intramolecular nucleophilic addition of aryl bromides to aldehydes, providing the corresponding cycloalkanol or cyclic ketone derivatives simply by changing the base or the ligand. Ten new 3,3‐dimethylchroman‐4‐ol derivatives and six new 3,3‐dimethylchroman‐4‐ones were prepared (with up to 91% conversion and 46% ee).
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