Red-Al^® Reducing Agent

Red-Al^®, or sodium bis(2-methoxyethoxy)aluminum dihydride (Vitride^®, SMEAH), is a versatile reducing agent and a good substitute for LiAlH₄ in many reactions. Red-Al^® is nonpyrophoric, although still moisture-sensitive, and is available in solution, allowing for easier handling compared to LiAlH₄.

Red-Al^® is particularly effective at the reduction of epoxides. A recent example employs Red-Al^® in a key step in the asymmetric synthesis of (R)-fluoxetine hydrochloride. The enantiomerically pure α,β-epoxyamide was reduced by Red-Al^® in the presence of 15-crown-5 to produce the β-hydroxyamide in good yield and excellent selectivity (Scheme 23).¹

Scheme 23

Cao and co-workers utilized Red-Al^® to convert propargyl chlorides to allenes, which were subsequently used in a tandem Pauson-Khand reaction to create 3,7-diisopropylsilyldicyclopenta-[a,e]pentalene, a 14π annulene (Scheme 24).²

Scheme 24

The preparation of highly functionalized α,β-disubstituted alkenoates can be achieved under mild conditions by reducing an acetylenic ester with Red-Al^® and quenching the reaction with iodine to yield the vinyl iodide. The vinyl iodide can be subsequently transformed via Sonogashira or Stille coupling to form the desired α,β-disubstituted alkenoates (Scheme 25).

Scheme 25

Red-Al^® displays excellent (E)-selectivity in the reduction and does not reduce the methyl ester.³ Red-Al^® reduction can selectively produce dialdehydes from aromatic diesters in the presence of N-methylpiperazine (Scheme 26). Although Red-Al^® is regularly employed in the reduction of esters to aldehydes, reduction of the diester without the addition of the amine produced only the dicarbinol.⁴

Scheme 26

References

1. Kakei H, Nemoto T, Ohshima T, Shibasaki M. 2004. Efficient Synthesis of Chiral?- and?-Hydroxy Amides: Application to the Synthesis of (R)-Fluoxetine. Angew. Chem. Int. Ed.. 43(3):317-320. https://doi.org/10.1002/anie.200352431

2. Cao H, et al. 2003. The Synthesis of a Dicyclopenta[a,e]pentalene via a Molybdenum Hexacarbonyl-Mediated Tandem Allenic Pauson−Khand Reaction. J. Am. Chem. Soc. 125:3230.

3. Meta CT, Koide K. 2004. Trans-Selective Conversions of γ-Hydroxy-α,β-Alkynoic Esters to γ-Hydroxy-α,β-Alkenoic Esters. Org. Lett.. 6(11):1785-1787. https://doi.org/10.1021/ol0495366

4. Hagiya K, et al. 2003. A Facile and Selective Synthetic Method for the Preparation of Aromatic Dialdehydes from Diesters via the Amine-Modified SMEAH Reduction System. Synthesis. 823.