Deoxygenative Reduction of Esters to Ethers and Alcohols

Author: Dr Philip Smith

In 2023, the Ramachandran Research group reported a Lewis acid-catalysed reduction of esters to ethers and alcohols, with selectivity between the two products controlled by the choice of Lewis acid catalyst. ^[1] This chemistry gives ethers in a single step from the corresponding esters without the need to alkylate an alcohol using a strong base and/or an electrophilic alkylating agent. By using TiCl₄ as the Lewis acid catalyst, formation of the corresponding alcohols was avoided; conversely when BF­₃OEt₂ was used as the catalyst, the alcohols were formed exclusively. The scopes for both reactions covered a range of aliphatic and aromatic esters, although it is notable that related work from the same authors suggests that other carbonyl functionalities, such as amides and carboxylic acids, would also likely be at least partially reduced under these conditions.^[2,3]

A summary of the mechanism proposed by the authors for this transformation is shown below. Carbon-13 NMR studies suggested that the reaction starts with coordination of the Lewis acid (TiCl₄ or BF₃Et₂O) to the carbonyl oxygen, followed by hydroboration of the carbonyl by borane-ammonia. Re-coordination of the Lewis acid to the acetal intermediate follows, and it is at this point that the choice of catalyst dictates the reaction outcome. The TiCl₄-catalysed reaction progresses to the ether by breaking the C-O bond to form an oxonium intermediate which is reduced by hydride addition. Using BF­₃Et₂O leads to elimination of an alkoxy group from the tetrahedral acetal intermediate to form an aldehyde which is hydroborated by borane-ammonia, giving an alcohol. The divergence of the two pathways is suggested to be due to the greater oxophillicity of TiCl₄ promoting formation of titanium oxychloride, with its strong Ti-O bond, at the expense of breaking a relatively weak C-O bond.

This chemistry was recently investigated at Apex Molecular as a potential route to several aromatic ether-containing targets; the chemistry was validated using a structure included in the original publication and applied to additional structures. In summary, this work is significant because it allows selectivity reduction of esters in contrast to well-established chemistry which is dominated by reduction to the alcohols.

References

1. V. Ramachandran, A. A. Alawaed, H. J. Hamann, Org. Lett. 2023, 25, 37, 6902–6906
2. V. Ramachandran, A. A. Alawaed, Molecules, 2023, 28, (12), 4575
3. V. Ramachandran, A. A. Alawaed, Molecules, 2023, 28, (1), 60