Direct remote C-H functionalization in piperidine derivatives

Projektinformationen

DiPipe

ID Finanzhilfevereinbarung: 837718

DOI

10.3030/837718

Projekt abgeschlossen

EK-Unterschriftsdatum 26 März 2019

Startdatum 1 April 2019

Enddatum 31 März 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 178 320,00

EU-Beitrag

€ 178 320,00

Koordiniert durch

UNIVERSITEIT ANTWERPEN
Belgium

Periodic Reporting for period 1 - DiPipe (Direct remote C-H functionalization in piperidine derivatives)

Berichtszeitraum: 2019-04-01 bis 2021-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The transition metal-catalyzed direct functionalization of C-H bonds is a major research topic across the world. However selective (regio-, enantio-, diastereoselective) and efficient functionalization of C(sp3)-H bonds remains a significant challenge: C(sp3)-H bonds are omnipresent in organic molecules and their dissociation energies are large. The use of directing groups (DGs) “guiding” the metal to specific C-H bond and allowing intramolecular C-H bond activation, is a recognized general approach to address the selectivity challenge. However, their installation and removal add steps to the overall reaction sequence. This project aims to develop unprecedented regio- and diastereoselective transition metal catalyzed functionalization of cyclohexyl and piperidine derivatives with haloalkenes making use of transient DGs and already installed DGs. Access to a large number of substituted piperidines as well as known and new bicyclic scaffolds can be achieved via post-functionalization of the vinylpiperidine reaction products, making the aimed synthetic methodology potentially suitable for molecular library synthesis in drug discovery. A particularly challenging objective of the project is the remote (meta) functionalization with respect to the DG at C3 of the piperidine ring. Piperidine is chosen as a central heterocycle core based on its importance in drug design and wide occurrence in commercial drugs (privileged scaffold).

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Orthogonal tandem catalysis with readily accessible aminocyclohexanes and gem-dibromoalkenes provided access to the bridged nitrogen bicyclic normorphan skeleton in a single step in a site- and diastereoselective manner. The one pot process involved a Pd-catalyzed -C(sp3)-H olefination of aminocyclohexane, equipped with a picolinamide directing group, followed by a consecutive ring closure reaction of the 1-bromo-1-alkenylated product via a Cu-catalyzed amidation. The tandem protocol featured broad scope as it can be applied on substituted aminocyclohexanes and aminoheterocycles, immediately providing access to the corresponding substituted, aza-and oxa-analogues of 7-alkylidenenormorphan without any further alteration. When no Cu catalyst was added, challenging regio- and diastereoselective Pd-catalyzed -C(sp3)-H olefination reactions with gem-dibromoalkenes was executed.
We also developed an efficient strategy for the cleavage of the picolinamide directing group (DG) and recycling of the byproduct. In this protocol, picolinamides were first Boc activated into tertiary N-Boc-N-substituted picolinamides. These were then cleaved via a Ni-catalyzed esterification reaction with EtOH to give valuable N-Boc protected amines. Ni(cod)2 was used as a catalyst without any ligands or base additives. The byproduct, ethyl 2-picolinate can be used to install the picolinamide DG in a direct or indirect manner on amines. The protocol exhibits a broad functional group tolerance and high yields. To demonstrate the utility of this approach, it was applied on many selected examples from the recent C−H functionalization literature featuring 2-picolinamide as a DG.

As a major dissemination result, one scientific publication has already been published. Another manuscript was submitted in Angew. Chem. Int. Ed. on 19th May, 2021. In order to communicate about the project to the public, a project blog on a social media was maintained (https://www.facebook.com/groups/dipipe). A video was published on YouTube (https://www.youtube.com/watch?v=45UO_TF4204&ab_channel=SovanBiswas). Both these actions target broad public and university students as well as broad (beyond the organic chemistry) research community.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Bridged bicyclic nitrogen scaffolds have a huge potential in drug discovery as these are conformational restricted analogues of important aminocarbo– and aminoheterocycles. However, long synthetic sequences relying on traditional organic chemistry currently limit the drug discovery process. New and shorter synthetic procedures are therefore required based on readily available starting materials. Several methods have been developed before for the construction of heterocyclic ring systems (e.g. indole, indoline, benzofuran etc.) via tandem reactions involving directed C(sp2)-H functionalization chemistry. However, procedures featuring a challenging directed C-C bond formation on unactivated C(sp3)-H are still rare. In this project, we developed the expedient formation of the normorphan core via a tandem catalysis approach involving intermolecular -C(sp3)-H olefination of DG equipped cyclohexanamines with 1,1-dibromo-1-alkenes followed by a ring closure reaction of intermediate 3-(1-bromo-1-alkenyl)cyclohexan-1-amine through a C(sp2)-Br amidation. This is a new, unknown in the state-of-the art approach to a construction of a bridged bicyclic nitrogen scaffold based on the C-H activation using a directing group (DG) with a potential impact on a drug discovery process in pharmaceutical industry.

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