Reduction compositions and processes for making the same

Details Reduction compositions and processes for making the same Reduction compositions and processes for making the same

1999-03-04

2002-09-03

Chang, Ceila (Department: 1625)

Chemistry of inorganic compounds

Hydrogen or compound thereof

C546S220000, C546S240000

Reexamination Certificate

active

06444190

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel compositions for reduction of organic substrates, and processes for preparing and using the same.
BACKGROUND OF THE INVENTION
There are a wide variety of reducing agents available for organic synthesis. For example, sodium borohydride, borane, lithium aluminum hydride and hydrogen are all employed to perform reductions industrially. Lithium aluminum hydride (LiAlH
4
) is a powerful reducing agent, soluble in organic solvents, and has found wide utility in organic synthesis. A wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitrites and imides. However, the expense of lithium aluminum hydride prevents its wider industrial employment.
A variety of synthetic methods exist for the commercial preparation of lithium aluminum hydride. One method involves the metathesis of sodium aluminum hydride (NaAlH
4
)with lithium chloride to form lithium aluminum hydride and sodium chloride (equation 1). Another method is the hydrogenation of a mixture of lithium (or lithium hydride) and aluminum to generate lithium aluminum hydride (equations 2 and 3). There are several others variations of equations 1-3 as well as from aluminum chloride and alkali salts and hydrides (equations 4 and 5). It should be noted that preparations of lithium aluminum hydride are never targeted for the preparation of a mixed alkali aluminum hydride such as a mixture of lithium and sodium aluminum hydrides.
LiCl+NaAlH
4
→LiAlH
4
+NaCl  1.
Li+Al+2H
2
→LiAlH
4
  2.
LiH+Al+3/2H
2
→LiAlH
4
  3.
4 NaH+AlCl
3
+LiCl→LiAlH
4
+NaCl  4.
4 LiH+AlCl
3
→LiAlH
4
+3NaCl  5.
All of these preparations are typically conducted in an organic solvent, such as toluene, diethyl ether, or tetrahydrofuran. Also, at the conclusion of the reaction, the reaction mixture is laboriously filtered to remove the unreacted starting materials and/or by-product inorganic salts. These filtrations are time consuming, the equipment is capital intensive, and some of the lithium aluminum hydride product adheres to the solids, which reduces the yield. The solid by-products and starting materials are very hazardous and must be handled, recycled, and quenched very carefully.
SUMMARY OF THE INVENTION
It has been discovered that a composition prepared from an active hydride, an additive, and a Lewis base, optionally in a hydrocarbon solvent, can provide a superior reducing system for organic substrates. For example, a composition prepared from 60 mole % tetrahydrofuran as the Lewis base, 10 mole % lithium chloride as the additive, 10 mole % sodium aluminum hydride as the active hydride, and 20 mole % toluene can afford excellent yields in standard organic reductions. In addition, the compositions of the invention are non-pyrophoric and are more thermally stable than pure THF solutions of sodium aluminum hydride (NaAlH
4
) or lithium aluminum hydride (LiAlH
4
).
The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less), typically from about thirty minutes to about four hours.
The present invention also provides processes for the reduction of organic substrates using the compositions of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Various active hydrides, including metal hydrides such as sodium aluminum hydride, trisodium aluminum hexahydride, and the like and mixtures thereof can be employed as the active hydride component. Examples of useful additives include, but are not limited to, lithium chloride, lithium bromide, aluminum trichloride, titanium tetrachloride, titanium tetrabromide, lithium alkoxides, lithium alkoxides of chiral alcohols (such as menthol), lithium dialkylamides, lithium dialkyl amides of chiral amines (such as (+) bis-[(R)-1-phenethyl]amine), and the like and mixtures thereof. Examples of useful hydrocarbon solvents include, but are not limited to, pentane, hexane, heptane, cyclohexane, decane, toluene, xylenes, ethylbenzene, cumene, cymene, and the like and mixtures thereof. Examples of useful Lewis bases include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl t-butyl ether (MTBE), 1,2-diethoxyethane, 1,2-dimethoxyethane, triethylamine, tributylamine, N, N, N′, N′-tetramethylethylenediamine (TMEDA), diisopropylethylamine, and the like and mixtures thereof.
Typical concentrations (mole %) of the components used to prepare the reducing composition of the invention are listed in the table below.
COMPONENT
MINIMUM
MAXIMUM
Lewis Base
45
80
Solvent
0
30
Additive
5
20
Hydride
5
20
The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less) for a few hours, typically from about thirty minutes to about four hours.
In one advantageous embodiment of the invention, the novel composition is prepared by adding a slurry of sodium aluminum hydride/toluene to a slurry of lithium chloride/tetrahydrofuran. Because the addition is very exothermic, care should be taken. When using the specific reagents sodium aluminum hydride and lithium chloride, the reagents must be combined in a precise manner to result in reduction product yields comparable to that of lithium aluminum hydride. Otherwise, reduction product yields comparable to that of sodium aluminum hydride result.
When using sodium aluminum hydride as a starting material, the composition of the invention is also unique as it is prepared from a slurry of sodium aluminum hydride in hydrocarbon solvent (i.e., about 80 weight percent (wt %) or less sodium aluminum hydride) and a minimal amount of tetrahydrofuran, in contrast to solid or damp cake forms of sodium aluminum hydride. For example, the slurry can be a commercially available slurry of 40 wt % sodium aluminum hydride in toluene. The use of a hydrocarbon solvent alone, such as toluene, without a Lewis base, such as tetrahydrofuran, can hinder the preparation of this effective, novel composition.
Although not wishing to be bound by any explanation of the invention, it is believed that the composition of the invention can include starting materials, counterion exchange products, complexes of starting materials and/or counterion exchange products, and mixtures thereof.
The novel reduction composition of this invention can also be characterized by its particle size distribution. For example, typical particle size distribution of a novel reduction composition in accordance with the invention prepared from 56.9 mole % tetrahydrofuran as the Lewis base, 15.7 mole % lithium chloride as the additive, 12.6 mole % sodium aluminum hydride as the active hydride, and 14.8 mole % toluene was determined on a Malvern MasterSizer. The mean diameter for the reduction composition is around 350 &mgr;m and the median is 400 &mgr;m. By comparison, the particle size distribution of sodium aluminum hydride exhibits a mean diameter at 216 &mgr;m and a median at 200 &mgr;m. The particle size distribution of lithium chloride exhibits a mean diameter at 424 ,&mgr;m and a median at 448 &mgr;m.
It has also been found that this same representative reduction composition slurry sample can be analyzed for sodium, lithium and aluminum by ICP (Inductively Coupled Plasma) and for chloride by wet titration. This data confirms the appropriate proportions of NaAlH
4
and LiCl combined during the preparation of this novel reduction composition. This is especially important when the sodium aluminum hydride charge cannot be accurately determined, for example, on large scale. Example ICP and chloride analyses are represented below. Chloride analysis is fa

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