Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights

Abstract

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds

“…In 2018, Kozlowski and co-workers reported the EH of α-(hetero)aryl pyridinium salts to the corresponding piperidines and investigated the reaction mechanism. 73 The EH of pyridinium salts with a heteroaryl functionality has not been widely reported. Previous reports have mainly focussed on α-phenyl derivatives without such a functionality.…”

Asymmetric hydrogenation for the synthesis of 2-substituted chiral morpholines

“… 6 It has been widely used as an “after cyclization” method for the efficient synthesis of various chiral N-heterocyclic compounds such as (benzo)piperidines and pyrrolidines. 7 However, to the best of our knowledge, there are only two literature examples concerning asymmetric hydrogenation for the synthesis of 3-substituted chiral morpholines, and only 73% ee was obtained for the endocyclic alkenyl substrates. 5 e , f ,8 In addition, an electron-withdrawing acyl substituent on the alkenyl was always required for the α-branched dehydromorpholines utilized in the asymmetric hydrogenation ( Fig.…”

Selective Arene Hydrogenation for Direct Access to Saturated Carbo‐ and Heterocycles

“…[9] The former motif (6)isofinterest in materials science for its high polarity;t he latter (7)c ombines two abundant design elements of medicinal chemistry.T he chemo-and enantioselective hydrogenation of pyridines is the key step within aconcise,multikilogram synthesis (7 steps,38%overall yield) of ap romising therapeutic against Ty pe 2d iabetes (8). [10] However,the implementation of this transformation towards ag iven target must satisfy three important conditions: 1) Reactivity:incontrast to the established hydrogenation of other unsaturated moieties such as alkenes, [11] ketones, [12] and imines/enamines, [13] the hydrogenation of arenes is hindered by the added kinetic barrier resulting from the aromatic stabilization energy. 2) Stereoselectivity:t he hydrogenation of multisubstituted arenes may form several product diastereomers;i ng eneral, the cis isomer is favored.…”