Chemoselective Reduction of Esters to Aldehydes by Potassium Diisobutyl-t-butoxyaluminum Hydride (PDBBA)

Abstract

The reduction of ester to aldehyde is one of the most useful synthetic transformations in organic synthesis, and a large number of reducing agents for this purpose have been reported. Among them, diisobutylaluminum hydride (DIBALH), which is commercially available, is used as one of the most popular reducing agents, although this reagent provides moderate yields (48-88%) and requires a very low temperature (−78 C). Very recently, we reported that lithium diisobutyl-t-butoxyaluminum hydride (LDBBA) and sodium diisobutyl-t-butoxyaluminum hydride (SDBBA), the alkoxy derivatives of DIBALH, were new partial reducing agents which could reduce various esters to aldehydes. Among them, LDBBA was especially effective for partial reduction of isopropyl esters to aldehydes in most cases with >90% yield at 0 C, and SDBBA was also effective for partial reduction of methyl and ethyl esters in very good yield (73-93%) at 0 C. As a part of our research program directed toward the discovery of new reducing agents through simple modification of commercial DIBALH, we recently found that potassium diisobutyl-t-butoxyaluminum hydride (PDBBA) was easily prepared by reacting an equimolar amount of potassium t-butoxide with DIBALH in THF at 0 C or room temperature (Scheme 1). We applied this reagent for the partial reduction of esters and nitriles to aldehydes. We first examined the partial reduction of representative esters and nitriles such as ethyl benzoate (entry 1 in Table 2), ethyl caproate (entry 15 in Table 2), benzonitrile (entry 19 in Table 2) and capronitrile (entry 20 in Table 2) with PDBBA in THF at 0 C. The reduction of these esters provides corresponding aldehydes in very good yield (88-89%) in 2448 h. In contrast, nitriles were not reduced at all. It was found that PDBBA essentially did not attack nitriles at 0 C. Therefore, partial reduction of esters to the correspondig aldehydes chemoselectively in the presence of nitriles was attempted. Indeed, as shown in Table 1, we achieved quantitative conversion of ethyl benzoate into benzaldehyde in mixtures with benzonitrile, with essentially no reduction of the benzonitrile. Accordingly, we applied PDBBA for the synthesis of aldehydes from various esters. The results for representative esters are summarized in Table 2. As shown in Table 2, ethyl benzoate was efficiently reduced to benzaldehyde in 89% yield (entry 1 in Table 2). Under identical conditions, reduction with DIBALH alone provided only benzyl alcohol (entry 2 in Table 2). Isopropyl benzoate need larger amount of hydride (1.5 eq) than sterically unhindered esters such as ethyl benzoate, presumably due to the bulky isopropyl group (entry 3 in Table 2). Also, esters of electron-withdrawing substituents such as ethyl 4fluorobenzoate, methyl 3-chlorobenzoate, ethyl 4-chlorobenzoate, ethyl 2-bromobenzoate, ethyl 4-bromobenzoate and ethyl 4-nitrobenzoate, and electron-donating substituents such as ethyl 2-toluate, ethyl 4-toluate and ethyl 4-methoxybenzoate were readily reduced to the corresponding aldehydes in 71-91% yield (entries 4-12 in Table 2). Among these, the reduction of ethyl 4-methoxybenzoate required a longer reaction time (48 h) than common esters. This may be attributed to the strong electron donating effect of the methoxy group. Similarly, reduction of other aromatic esters such as ethyl 2-naphthalate, a poly-aromatic ester and ethyl 2-furoate, a heterocyclic ester gave the corresponding aldehydes in 88% and 84% yield, respectively (entries 13 and 14 in Table 2). Furthermore, aliphatic esters such as ethyl caproate, isopropyl caproate, ethyl undecanoate and ethyl cyclohexanecarboxylate were efficiently reduced to the corresponding aldehydes in 78-90% yield (entries 15-18 in Table 2). In summary, we easily prepared PDBBA by reacting commercially available DIBALH with potassium t-butoxide.