UC Santa Cruz

Selective, partial, or tandem reductions of bifunctional compounds containing primary alkyl or benzyl bromides can generate a variety different of products using a mixture of dichloroindium hydride (HInCl2) and an additional hydride, such as borane-tetrahydrofuran (BH3:THF) or diisobutylaluminum hydride (DIBAL-H). Binary metal hydride systems, containing HInCl2 and BH3:THF, are readily generated from anhydrous indium trichloride (InCl3) and sodium borohydride (NaBH4) in THF. Dichloroindium hydride can reduce a variety of primary halides and in the presence of another hydride, either generated in situ or added to the single-pot reaction, which allows for the tandem reduction of a variety of bifunctional bromides. Together, the hydrides reduce carbon-halogen bonds as well as an electrophilic group, such as a nitrile, ester, or carboxylic acid. The reduction of 4-(bromomethyl)benzonitrile using the HInCl2 and BH3:THF binary metal hydride system affords 4-methylbenzylamine in excellent yield under ambient conditions and short reaction times. By using the binary metal hydride system consisting of HInCl2 and DIBAL-H, the tandem reduction of 4-(bromomethyl)benzonitrile was achieved affording para¬-tolualdehyde in excellent yield, also under ambient conditions. Reduction of 4-(bromomethyl)phenyl acetic acid by HInCl2 selectively reduced the carbon-halogen bond generating para-tolylacetic acid. When using either binary hydride system, both functional groups are reduced generating 4-methylphenethyl alcohol. Methyl 4-(bromomethyl) benzoate underwent a selective or tandem reduction to generate [4-(bromomethyl)phenyl]methanol, methyl 4-methyl benzoate or para-tolylmethanol depending on the hydride system used. Consequently, a single bifunctional compound is transformed to a variety of different compounds by simple manipulation of the binary hydride system used without the need of protecting groups, and in most cases, a one-pot procedure.

A new reducing agent has been developed for the reduction of tertiary amides under ambient conditions. A synthetically simple mixed metal hydride, diisobutylaluminum borohydride [(iBu)2AlBH4], is easily generated from a 1:1 mixture of borane-dimethylsulfide (BMS) and diisobutylaluminum hydride (DIBAL). Tertiary aliphatic and aromatic amides as well as lactams are reduced to the corresponding amine in five minutes under ambient conditions using (iBu)2AlBH4. The enhanced reactivity is due to the mixed hydride reagent acting in a synergistic fashion through a push-pull activation of the amide by a Lewis acid-hydride interaction, allowing the reduction to proceed smoothly. The product is obtained through a simple acid-base extraction work-up and does not require any column chromatography technique for the isolation or purification of the amine in yields of 71 to 99%. After the reduction is complete, addition of methanol converts aluminum containing compounds to a solid polymer, which is removed through simple filtration. This new methodology works well for aliphatic and aromatic amides as well as lactams.