Abstract of Patent US5675038
The invention is directed to a process for reducing or reductively cleaving an organic compound susceptible to dissolving metal reduction comprising exposing the organic compound to a solution of lithium in a polyamine including at least two amino groups, selected from the group consisting of primary and secondary amino groups and mixtures thereof, e.g. ethylenediamine and R-NH2, optionally containing a lower alkyl alcohol, wherein R is chosen from the group consisting of ethyl, propyl, and butyl, including all straight and branched chain isomers thereof, for a time sufficient to effect reduction.
DETAILED DESCRIPTION OF THE INVENTIONPreliminary experiments with lithium in lower alkyl amines alone, such as in n-propylamine or isopropylamine made clear that reduction is very slow and subsequently the yields are not as high. Essentially the reaction does not proceed without the addition of a polyamine, such as ethylenediamine, to the reaction mixture. The addition results in reaction times that are faster than comparable reductions done under Birch conditions or lithium in amine (Benkeser) conditions. At least one mole of polyamine, e.g. ethylenediamine, per gram atom of lithium is used in reactions utilizing the processes of the present invention, optionally more than one equivalent may be added. The present invention may be carried out without any hydroxylic Solvent, but in some reactions, an added hydroxylic solvent, such as t-butanol, may be beneficial to the yield of a desired product or isomer of a product. Addition of an alcohol provides a source of protons more acidic than the amine groups present in the reaction solution. This can assist in protonation of intermediates or products in the reaction and so speed the reaction, reduce formation of unwanted by-products or isomers, or allow the reduction to proceed beyond that which would occur without protonation of an intermediate. One skilled in the art can determine when such addition is beneficial, either through the analysis of the predicted reaction mechanism or through experimentation.
The following examples are mechanistically very similar to the reduction of pseudoephedrine, and should be studied in more detail:EXAMPLE 5Reduction of anisole. Lithium, in small pieces, (8.75 g, 1.25 gram-atoms) was added to a solution of anisole (54 g, 0.5 mol) in n-propylamine (400 mL), ethylenediamine (105 g (1.75 mol) and t-butanol (111 g, 1.5 mol) cooled to -18 DEG . The temperature increased to 12 DEG and then decreased to -5 DEG . After 2 hr all of the lithium had reacted and the reaction mixture was diluted with 800 mL of water added slowly. The mixture was extracted with ether (3.times.250 mL). The ether extracts were washed with water (3.times.200 mL) and brine (1.times.100 mL) and evaporated. The residue was distilled to give 27.5 g (50% of 1-methoxy-1,4-cyclohexadiene containing 10% of 1-methoxy-1,3-cyclohexadiene by glpc and nmr.
EXAMPLE 6Reduction of naphthalene. Lithium (3.5 g, 0.5 gram-atom), in small pieces, was added in one portion to a solution, cooled to -16 DEG , of naphthalene (12.8 g, 0.10 mol) in n-propylamine (100 mL), ethylenediamine (30 g, 0.5 mol) and t-butanol (44.4 g, 0.6 mol). The solution warmed to 45 DEG and cooled to 0 DEG in 15 min. After 15 min, the reaction mixture was poured over 150 g of ice and 100 mL of water and then extracted with ether (3.times.150 mL). The ether was washed with water (2.times.100 mL) and brine (1.times.100 mL). The ether was evaporated under reduced pressure to give 12.2 g of a colorless solid which was triturated with methanol, filtered and dried to give crude 1,4,5,8-tetrahydronaphthalene which was crystallized from methanol (25 mL) to give 8.6 g (65%) of 1,4,5,8-tetrahydronaphthalene which was 93% pure by glpc.