10.1002/chem.202000060
Chemistry - A European Journal
COMMUNICATION
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This synthetic sequence is operationally simple and delivers
products bearing multiple new functional groups, such as an
activated electron-deficient alkene and a primary alcohol, allowing
many possibilities for the additional functionalization reactions
which are essential for structure-activity relationship studies.
Furthermore, in part due to the relatively mild conditions for
transition-metal catalysis (45 °C and a mild base), a wide range
of potentially sensitive functional groups, such as cyclic imides,
aromatic halides, enolizable ketones, electron-rich heterocycles,
and aromatic ethers, were all tolerated under reaction conditions
and do not hinder the catalytic reaction.
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Mechanistically, we believe the reaction proceeds under a
pathway that is depicted in Scheme 5.3a Addition of methanol to
formaldehyde generates hemiacetal 5, which is then oxidized by
iridium to generate methyl formate and an iridium-hydride species.
Addition of iridium-hydride occurs at the C2-position of 1a due to
the presence of the electron-withdrawing heterocycle in the C4
position, resulting in the formation of enamine 6. The trapping of
formaldehyde by 6, leads to the formation of a new carbon-carbon
bond and the iminium 7, which is readily reduced by a second
equivalent of iridium-hydride to furnish product 2a. Supporting this
1
pathway, H NMR analysis of the crude reaction indicated the
presence of formate by-products, consistent with the oxidation of
formaldehyde.
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Scheme 5: Proposed mechanistic pathway
In conclusion, we have developed the iridium-catalyzed reductive
hydroxymethylation of activated 4-heteroaryl pyridines, giving rise
to highly useful decorated 4-heteroarylpiperidines using methanol
and formaldehyde as reagents. The methodology has been used
in the late stage preparation of medicinally relevant scaffolds
demonstrating its importance for medicinal chemistry and its
tolerance of a wide range of functional groups. In our laboratory
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substrates which have the potential to be proficient in this
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Acknowledgements
TJD thanks the EPSRC (EP/L023121/1) for funding. HBH thanks
the European Commission for a Marie Skłodowska-Curie Actions
fellowship (Grant: 792562 H2020-MSCA-IF-2017).
Keywords: iridium, hydroxymethylation, aromatic heterocycles,
reductive functionalization.
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