1016970-61-8Relevant articles and documents
Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis
Duttwyler, Simon,Chen, Shuming,Takase, Michael K.,Wiberg, Kenneth B.,Bergman, Robert G.,Ellman, Jonathan A.
, p. 678 - 682 (2013)
Piperidines are prevalent in natural products and pharmaceutical agents and are important synthetic targets for drug discovery and development. We report on a methodology that provides highly substituted piperidine derivatives with regiochemistry selectively tunable by varying the strength of acid used in the reaction. Readily available starting materials are first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation of the dihydropyridines under either kinetic or thermodynamic control provides two distinct iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions. X-ray structural characterization of both the kinetically and thermodynamically favored iminium ions along with density functional theory calculations provide a theoretical underpinning for the high selectivities achieved for the reaction sequences.
Preparative Synthesis of Highly Substituted Tetrahydropyridines via a Rh(I)-Catalyzed C-H Functionalization Sequence
Mesganaw, Tehetena,Ellman, Jonathan A.
, p. 1105 - 1109 (2014)
We report a Rh(I)-catalyzed C-H activation/alkenylation/electrocyclization cascade and subsequent reduction for the synthesis of highly substituted tetrahydropyridines. These products can be accessed on a gram scale with low catalyst loadings and at high reaction concentrations. Additionally, a modified Rh-catalyst, prepared from [RhCl(cod)]2 as a robust bench-stable precatalyst was developed to enable straightforward reaction set up without the use of a glovebox. To demonstrate the practicality of this reaction, a >100 mmol scale Rh-catalyzed cascade reaction sequence utilizing the air-stable precatalyst [RhCl(cod)]2 was performed on the bench to furnish the pure tetrahydropyridine product in 93% yield.
Highly diastereoselective synthesis of tetrahydropyridines by a C-H activation-cyclization-reduction cascade
Duttwyler, Simon,Lu, Colin,Rheingold, Arnold L.,Bergman, Robert G.,Ellman, Jonathan A.
supporting information; experimental part, p. 4064 - 4067 (2012/04/10)
A versatile reaction cascade leading to highly substituted 1,2,3,6-tetrahydropyridines has been developed. It comprises rhodium(I)-catalyzed C-H activation-alkyne coupling followed by electrocyclization and subsequent acid/borohydride-promoted reduction. This one-pot procedure affords the target compounds in up to 95% yield with >95% diastereomeric purity.
Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation
Colby, Denise A.,Bergman, Robert G.,Ellman, Jonathan A.
, p. 3645 - 3651 (2008/10/09)
A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been developed for the synthesis of highly substituted pyridine derivatives from alkynes and α,β-unsaturated N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be achieved with previously reported ligands. Substantial information was obtained about the mechanism of the reaction. This included the isolation of a C-H activated complex and its structure determination by X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination steps.
