Reduction of a ketone in the presence of an aldehyde

Question

An aldehyde group can easily be reduced to an alcohol using the mild reducing agent $\ce{NaBH4}$ at low temperature in the presence of a ketone group. This chemoselectivity is due to the fact that an aldehyde is less sterically hindered compared to a ketone, which makes it react faster than the ketone.

Is it possible, however, to chemoselectively reduce a ketone in the presence of an aldehyde using $\ce{NaBH4}$ as reducing agent?

Answer 1

The best strategy is probably to chemoselectively protect the aldehyde before the borohydride reduction. Protecting groups are derivatives of certain moieties in a molecule that are far less reactive under most conditions, but which can be easily removed under very specific conditions to regenerate the original moiety.

For carbonyl compounds -- this includes both aldehydes and ketones -- the most common protecting groups are all introduced by ketalization/acetalization. Common examples are dimethyl acetals, 1,3-dioxolanes, and 1,3-dioxanes.

However, in general, aldehydes are far more prone to acetalization than ketones are to ketalization. That offers a means to chemoselectively protect aldehydes. Acetals such as 1,3-dioxanes are stable to borohydride reductions, but, as you note in your question, ketones are sensitive.

Poking around reveals several potential strategies for selective chemoprotection of an aldehyde. Here are two examples.

• Tetrabutylammonium Tribromide (TBATB) as An Efficient Generator of HBr for an Efficient Chemoselective Reagent for Acetalization of Carbonyl Compounds:

  This convenient, mild, chemoselective method allows acetalization of an aldehyde in the presence of ketone...

• Chemoselective Protection of Aldehydes in the Presence of Ketones Using RuPVP Complex as a Heterogeneous Catalyst

Putting it all together, a recipe for selective borohydride reduction of a ketone in the presence of an aldehyde would be something like:

1. Protect the aldehyde. The best choice is probably as a 1,3-dioxane acetal by reacting your compound with 4 equivalents of 1,3-propanediol, 1 equivalent of triethyl orthoformate, and 0.01 equivalent of tetrabutylammonium tribromide. Under suitable conditions, the ratio of protected aldehyde (desired) to protected ketone (undesired) should be >50.

2. Borohydride reduction of the aldehyde-protected compound. Only the unprotected ketone will react.

3. Deprotection. Acetals can be removed in acidic conditions. A number of catalysts that will effect deprotection without requiring acid have also been developed.

Answer 2

An easy and convenient method to achieve this is the use of the Luche reduction.^[1,2]

The ‘organic chemist’s bible’, Strategic Applications of Named Reactions in Organic Synthesis by L. Kürti and B. Czakó notes on the page of the Luche reduction (p. 268):

8) the combination of $\ce{CeCl3/NaBH4}$ is excellent for the chemoselective reduction of ketones in the presence of aldehydes, since under these conditions aldehydes undergo rapid acetalization, which prevents their reduction.

Indeed, when a $1:1$ mixture of hexanal and cyclohexanone is subjected to Luche conditions with $1.5~\mathrm{eq}$ of $\ce{NaBH4}$, a quantitative yield of cyclohexanol and a nigh-quantitative ($98~\%$) of hexanal are recovered. Without the addition of $\ce{CeCl3}$, $1.5~\mathrm{eq}$ reduce cyclohexanone quantitatively and $49~\%$ of hexan-1-ol are also recovered.^[1]

---

Reference and note:

[1]: J. L. Luche, A. L. Gemal, J. Am. Chem. Soc. 1979, 101, 5848. DOI: 10.1021/ja00513a075.

[2]: The article [1] is only two pages short. The first page is displayed as an ‘abstract’ on pubs.acs.org (‘in lieu of an abstract’, ibid.). Thus, opening the abstract of S. Nagase, T. Fueno, K. Morokama, J. Am. Chem. Soc. 1979, 101, 5849 (DOI: 10.1021/ja00513a076) can serve as a cheap hack to see the entire article.