Abstract
Enantioenriched, six-membered azacycles are essential structural motifs in many products of pharmaceutical or agrochemical interest. Here we report a simple and practical method for enantioselective assembly of tetrahydropyridines, which is paired to a kinetic resolution of α-branched allyltriflamides. The reaction consists of a formal (4+2) cycloaddition between the allylamine derivatives and allenes and is initiated by a palladium(II)-catalyzed C–H activation process. Both the chiral allylamide precursors and the tetrahydropyridine adducts were successfully obtained in high yields, with excellent enantioselectivity (up to 99% ee) and selectivity values of up to 127.
Highlights
Enantioenriched, six-membered azacycles are essential structural motifs in many products of pharmaceutical or agrochemical interest
One of the most relevant approaches to generate asymmetry consists of the desymmetrization of prochiral C−H bonds using palladium catalysts and monoprotected amino acids as metal ligands, a strategy that was pioneered by the group of Yu.[3]
We have recently published a palladium-catalyzed desymmetrization of diarylmethanamine triflamides by reaction with allenes to form chiral tetrahydroisoquinolines.3e these methodologies are appealing, they require the presence of symmetric groups in the molecule, which represents a significant restriction in terms of the structural variability that can be achieved
Summary
Amine (S)1a can be alkylated with propargyl bromide, and the resulting enyne can be cyclized to the interesting piperidine 9 using iridium catalysis This optically active product (99% ee), obtained as a single diastereoisomer, exhibits up to four stereocenters.[9] we demonstrated that enantioenriched compounds like (S)-1a can participate in the (4+2) annulation reaction with allene 2a under standard conditions, using the D-amino acid ligand derivative, to give the corresponding enantiomer (S)-3aa (88% yield), which exhibit the same enantiomeric excess as the starting material. The reaction allows very efficient kinetic resolutions and provides an unprecedented access to a broad range of enantioenriched piperidines and highly substituted allyl amines These enantioenriched products can be converted into several appealing azacycles and different nitrogenated derivatives.
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