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Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines
Author(s) -
Subota Andrii I.,
Lutsenko Anton O.,
Vashchenko Bohdan V.,
Volochnyuk Dmitriy M.,
Levchenko Vitalina,
Dmytriv Yurii V.,
Rusanov Eduard B.,
Gorlova Alina O.,
Ryabukhin Sergey V.,
Grygorenko Oleksandr O.
Publication year - 2019
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201900450
Subject(s) - chemistry , yield (engineering) , piperidine , metalation , prins reaction , ring (chemistry) , catalysis , adduct , retrosynthetic analysis , stereochemistry , medicinal chemistry , organic chemistry , combinatorial chemistry , total synthesis , materials science , metallurgy
An efficient approach towards introducing (cyclo)alkyl substituents at C‐2, C‐3 or C‐4 positions of the piperidine ring was described. The method relied on the straightforward two‐step reaction sequence based on the formal sp 3 –sp 3 retrosynthetic disconnection. The procedure commenced with selective directed ortho metalation of 2‐ and 3‐bromopyridine, followed by reaction with aldehydes or ketones. The optimized methods were developed for all three isomers of hydroxyalkyl‐substituted pyridines, which were synthesized in 28–84 % overall yield (20 examples). Catalytic hydrogenation of these adducts could be performed selectively with or without retention of the hydroxyl group in their molecules, so that either (cyclo)alkylpiperidines (14 examples) or the corresponding saturated amino alcohols (16 examples) were obtained (28–96 % and 82–96 % yield, respectively). After minor modifications, the developed method was also implemented in a flow reactor and a 5 L autoclave, which allowed for the preparation of up to 0.5 kg of the representative (cyclo)alkylpiperidines.