Organic compounds -- part of the class 532-570 series – Organic compounds – Boron containing
Reexamination Certificate
1999-05-25
2001-07-31
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Boron containing
C568S006000, C568S007000
Reexamination Certificate
active
06268537
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of synthesis of lithium substituted borohydride reagents and to a method of synthesis of lithium hydride, and, more particularly, to a method of synthesis of sterically hindered lithium substituted borohydride reagents and to a method of synthesis of lithium hydride from an alkyl lithium compound in the presence of tetrahydrofuran.
BACKGROUND OF THE INVENTION
Since the early 1970's there has been a strong interest in synthesizing alkali metal trisubstituted borohydride reagents because of their unique reactivity and synthetic utility in organic chemistry. Lithium trisubstituted borohydrides reagents, for example, are used in organic synthesis primarily as regioselective and stereoselective borohydride reducing agents. Most preparations of lithium trisubstituted borohydrides have focused on the reaction of lithium hydride or lithium aluminum reagents and trialkyl boranes to produce the above mentioned compounds. The reaction formula below represents the reaction of lithium hydride and a trisubstituted borane.
Unfortunately, there has been little success in synthesizing sterically hindered lithium trisubstituted borohydride reagents from commercially available lithium hydride and corresponding sterically hindered trisubstituted boranes. Indeed, a number of investigators have noted that hindered and highly hindered trisubstituted boranes are essentially inert towards lithium hydride. See, for example, Brown, H. C. et al.,
J. of Organometallic Chem.,
166, 27-280 (1979); Brown, H. C. et al.,
J. of Organometallic Chem.,
188, 1-10 (1980); Brown, H. C.,
Tetrahedron,
37, 2359-2362 (1981); and Thompson, et al.,
J. Org. Chem.,
44:26, 5004-5005 (1979).
It is believed that processed or commercially available lithium hydrides are not highly reactive in such reactions. Even with special washing and activating procedures, sterically hindered trisubstituted borohydrides (for example, lithium tri-sec-butylborohydride) cannot be produced in commercially viable yields from commercially available lithium hydrides. In that regard, the yields from such reactions are less than 10% in 24 hours based upon the amount of the limiting reagent consumed in the reaction.
There are some indication that lithium hydride (LiH) formed in situ, may be more reactive toward sterically hindered substituted boranes than commercially available LiH. For example, it is known that n-butyl lithium slowly thermally decomposes by evolution of 1-butene and precipitation of LiH.
J. Org. Chem,
30, 4138 (1965). The generation of LiH from n-BuLi is more efficient by hydrogenation of n-BuLi in the presence of tetramethylethylenediamine (TMEDA).
J. Am. Chem. Soc.,
60, 2336 (1938);
J. Am. Chem. Soc.,
88, 5668 (1966); and
J. Am. Chem. Soc.,
52, 4299 (1987). One literature report indicated that LiH produced by this method with one equivalent of TMEDA was of sufficient reactivity to react with tri-sec-butylborane to generate lithium tri-sec-butylborohydride. Andres, H.,
Synthesis and Applications of Isotopically Labeled Compounds,
40-45 (1991); and 83-90, (1994). The present inventors have discovered, however that TMEDA, even when used in catalytic amounts, imparts impurities in the lithium trialkylborohydride which are detrimental to intended usage.
It is very desirable, therefore, to develop commercially viable methods of producing sterically hindered lithium substituted borohydride reagents that do not suffer from the problems associated with current synthetic routes.
SUMMARY OF THE INVENTION
The present invention provides a method of synthesizing sterically hindered lithium tri-substituted compounds (for example, compounds having the formula Li[R
1
R
2
R
3
B]H, wherein R
1
, R
2
and R
3
, wherein R
1
, R
2
and R
3
are independently, the same or different). As used herein, the phrase “hindered lithium trisubstituted borohydride compounds” refers generally to sterically hindered compounds wherein the boron atom is attached to a secondary carbon or a tertiary carbon on at least two of substituents R
1
, R
2
and R
3
. If the boron is attached to two substituents via tertiary carbons, the third substituent should be attached to the boron via a primary carbon. Neither of the two substituents attached to the boron atom via a tertiary carbon should be substituted at the &agr;-carbon. As used herein, the term &agr;-carbon refers to the carbon adjacent the carbon attached to the boron. If the boron is attached to two substituents via secondary carbons, the third substituent may be attached to the boron via a secondary carbon or a primary carbon. If all three substituents are attached to the boron via secondary carbons, none of the substituents should be substituted at the &agr;-carbon. If two of the three substituents are attached to the boron via secondary carbons, one of these substituents can be substituted at the &agr;-carbon. Lithium tri-substituted compounds that are more hindered than those described above are considered to be “highly” hindered.
R
1
, R
2
and R
3
can, for example, be independently alkyl or aryl groups. In one embodiment, the substituents are alkyl groups (for example, unbranched, branched, cyclic or acyclic secondary alkyl groups). Specific examples, of tri-sec-alkylborohydride compounds synthesized via the present method include lithium tri-sec-butylborohydride, lithium B-hexyl-9-boratabicyclo[3.3.1]nonane and lithium B-cyclohexyl-9-boratabicyclo[3.3.1]nonane.
In general, the method comprises the step of reacting lithium hydride and a sterically hindered trisubstituted borane in a reaction vessel to produce the hindered lithium trisubstituted borohydride compound. As used herein, the terms “lithium hydride or LiH” encompass isotopes including LiH (wherein lithium is bonded to hydrogen), LiD (wherein lithium is bonded to deuterium) and LiT (wherein lithium is bonded to tritium). The reaction temperature is preferably maintained in a temperature range of approximately 15° C. to approximately 42° C. during a period of time. The period of time is preferably at least approximately 20 minutes. More preferably, the reaction is maintained in a temperature range of approximately 20° C. to approximately 35° C. for a period of time. Even more preferably, the reaction is commenced in a temperature range of approximately 15° C. to approximately 42° C. Still more preferably, the reaction is commenced in a temperature range of approximately 20° C. to 35° C.
Preferably, the lithium hydride and the trisubstituted borane substrate are of relatively high purity. In that regard, the purity of the lithium hydride is preferably at least approximately 80%. More preferably, the purity of the lithium hydride is at least approximately 95%. Most preferably, the purity of the lithium hydride is at least approximately 98%. The purity of the trisubstituted borane is preferably at least approximately 85% relative to other boron species. More preferably, the purity of the trisubstituted borane is at least approximately 90%. Most preferably, the purity of the trisubstituted borane is at least approximately 95%. Tetrahydrofuran is preferably used as a solvent for the reaction. In a preferred embodiment, the lithium substituted borohydride product is lithium tri-sec-butlylborohydride.
The present inventors have discovered that yields of sterically hindered lithium trisubstituted borohydrides in excess of 10% (in 24 hours based upon the limiting reagent in the reaction) can be achieved in the present method with lithium hydride reactants with which such yields were not previously possible. Indeed, commercially viable yields of such hindered lithium trisubstituted borohydrides are possible in the present invention with processed lithium hydride reagents, which include all commercially available lithium hydrides. As used herein, the phrase “processed lithium hydride reagent” refers generally to lithium hydride reagents that have been subjected to processing such as particle size reduction or removal of a liquid reaction matrix. Su
Bruening Joerg
Burkhardt Elizabeth R.
Rouda David F.
Sutton Christopher P.
Bartony, Jr. Henery E.
Mine Safety Appliances Company
Uber James G.
Vollano Jean F.
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