A zirconium
catalyzed reductive cleavage of Csp3
and Csp2
carbon–heteroatom bonds is reported that
makes use of a tethered alkene functionality as a traceless directing
group. The reaction is successfully demonstrated on C–O, C–N,
and C–S bonds and proposed to proceed via a hydrozirconation/β-heteroatom
elimination sequence of an in situ formed zirconium hydride catalyst.
The positional isomerization of the catalyst further enables the cleavage
of homoallylic ethers and the removal of terminal allyl and propargyl
groups.
This work introduces a catalytic zirconium chain-walk reaction that in combination with a β-heteroatom elimination step enables the cleavage of remote nonactivated carbon−heteroatom bonds. The result is a controlled defunctionalization reaction, which takes place with excellent site selectivity and can be applied to symmetrical and unsymmetrical alkene chains with ether, amine, and thioether groups. The approach can be used for remote functional group substitution as well, and a preliminary investigation indicates a dissociative chain-walk mechanism.
A catalytic enantioselective β‐O‐elimination reaction is reported in the form of a zirconium‐catalyzed asymmetric opening of meso‐ketene acetals. Furthermore, a regiodivergent β‐O‐elimination is demonstrated. The reaction proceeds under mild conditions, at low catalyst loadings, and produces chiral monoprotected cis‐1,2‐diols in good yield and enantiomeric excess. The combination with a Mitsunobu reaction or a one‐pot hydroboration/Suzuki reaction sequence then gives access to additional diol and aminoalcohol building blocks. A stereochemical analysis supported by DFT calculations reveals that a high selectivity in the hydrozirconation step is also important for achieving high enantioselectivity, although it does not constitute the asymmetric step. This insight is crucial for the future development of related asymmetric β‐elimination reactions.
Herein, we report on the discovery and development of novel cascade N−N bond forming reactions for the synthesis of rare indazole acetic acid scaffolds. This approach allows for convenient synthesis of three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) by heating 3‐amino‐3‐(2‐nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions. The reaction tolerates a range of functional groups and electronic effects and, in total, 23 novel indazole acetic acids were synthesized and characterized. This work offers a valuable strategy for the synthesis of useful scaffolds for drug discovery programs.
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