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(12) Patent Application Publication (10) Pub. No.: US 2014/0306153 A1 LEFENFELD Et Al US 201403 06153A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0306153 A1 LEFENFELD et al. (43) Pub. Date: Oct. 16, 2014 (54) LITHIUM-POROUS METAL OXDE (60) Provisional application No. 60/824,964, filed on Sep. COMPOSITIONS AND LITHIUM 8, 2006. REAGENT-POROUS METAL COMPOSITIONS (71) Applicants: SIGNACHEMISTRY, INC., New York, NY (US); BOARD OF Publication Classification TRUSTEES OF MICHGAN STATE UNIVERSITY, East Lansing, MI (US) (51) Int. Cl. C07F I/02 (2006.01) (72) Inventors: Michael LEFENFELD, New York, NY (US); James L. DYE, East Lansing, MI (52) U.S. Cl. (US); Partha NANDI, East Lansing, MI CPC ........................................ C07F I/02 (2013.01) (US); James JACKSON, Haslett, MI USPC ..................................................... 252A182.12 (US) (73) Assignees: SIGNACHEMISTRY, INC., New (57) ABSTRACT York, NY (US); BOARD OF TRUSTEES OF MICHGAN STATE The invention relates to lithium reagent-porous metal oxide UNIVERSITY, East Lansing, MI (US) compositions having RLi absorbed into a porous oxide. In (21) Appl. No.: 14/257,361 formula RLi, R is an alkyl group, an alkenyl group, an alkyny group, an aryl group, an alkaryl group, oran NR'R' group; R' (22) Filed: Apr. 21, 2014 is an alkyl group, an alkenyl group, an alkynyl group, an aryl Related U.S. Application Data group, an alkaryl group; and R is hydrogen, an alkyl group, (62) Division of application No. 13/469,299, filed on May an alkenyl group, an alkynyl group, an aryl group, and an 11, 2012, now abandoned, which is a division of ap alkaryl group. The preparation and use of lithium reagent plication No. 1 1/852,820, filed on Sep. 10, 2007, now porous metal oxide compositions having RLi absorbed into a Pat. No. 8,197,707. porous oxide compositions are also described. 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This side reaction can RELATED CASE INFORMATION be nearly eliminated by using cold temperatures or chlorine or bromine as the halogen. Other methods of creating orga 0001. This application claims priority to U.S. Provisional nolithium reagents include, for example: (i) reacting a Patent Application No. 60/824,964, filed Sep. 8, 2006, which organic halide with a radical anion lithium salt, (ii) perform is hereby incorporated by reference in its entirety. ing a metal-halogen exchange between an organic halogen FIELD OF THE INVENTION compound, and an organolithium species (e.g. Gilman, H. et. al. J. Am. Chem. Soc. 1932; 54, 1957), (iii) an exchange 0002 This invention relates to lithium metal-porous oxide between an organolithium species and another organometal compositions made by the interaction of metallic lithium with lic compound, (iv) the deprotonation of an organic compound porous metal oxide powders, such as alumina gel, and their with an organolithium reagent, (v) reductive cleavage of the use to prepare organolithium and lithium amide reagents, carbon-heteroatom (such as Sulfur, oxygen, phosphorus, or both in situ and as solid free flowing easily handled and stored silicon) bonds (e.g., Gilman, H., et. al., Org. Chem. 1958; 23. materials. These compositions do not require flammable sol 2044.), or (vi) lithium-hydrogen exchange from LiOH and vents and/or cold conditions for storage, shipment and use, toluene to make benzyl lithium in DMSO (U.S. Patent Appli yet the absorbed lithium and lithium reagents retain their cation Publication No. 200601701 18 by Everett et al.). reactivity and synthetic utility. 0007 Organolithium reagents, specifically butyllithium (Bulli), methyllithium (Meli), phenylithium (PhLi), and BACKGROUND OF INVENTION others, are widely used as chemical building blocks and as 0003 Organolithium and lithium amide compounds are strong bases in both the pharmaceutical and the industrial important reagents used routinely in synthetic chemistry manufacturing industry. Lithium amides find related applica transformations. Traditionally, organolithium reagents are tions; for example, lithium diisopropylamide (LDA) and made by combining finely divided lithium metal at low tem lithium hexamethyldisilazide (LiHMDS) are both strong: perature with solutions of haloorganics or by metal-halogen bases that are also capable of performing enantioselective exchange reactions. Lithium amides are most commonly pre alkylation by virtue of the strong coordinating ability of pared by the deprotonation of amines using an organolithium lithium (Hilpert, H. Tetrahedron, 2001, 57, 7675). Carbon reagent. However, stability, storage, and handling of organo centered organolithiums, such as nBuLi, are considered to be lithium compounds remain problems that often make their both powerful nucleophiles and strong bases at the same time. use difficult for organic synthesis, including their use to make (Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; lithium amides. Volante, R. P.; Shinkai, I.J. Org. Chem. 1992, 57, 2771). 0004 Organolithium as used herein, and as commonly These characteristics enable their use as initiators for anionic used in the art, refers to lithium compounds of carbon-cen polymerizations (Hungenberg, Klaus-Dieter; Loth, Wolf tered anions. Organolithium reagents are synthetically useful gang; Knoll, Konrad; Janko, Lutz; Bandermann, Friedhelm, because they are strong bases, effective nucleophiles, and Method for producing statistical styrene-butadiene copoly effective catalysts for radical and anionic polymerizations. mers. PCT Int. Appl. WO9936451 A1. Such reagents are, however, very reactive, often spontane 0008 Little can be done to modify the reactivity or selec ously catching fire in the presence of air. To control these tivity of ordinary organolithium and lithium amide reagents, hazards, they are only commercially available as solutions in yet modification is a growing need in many chemical indus hydrocarbon or ether solvents. These solvents can moderate tries, especially for pharmaceutical and polymerization pro the pyrophoric nature of the organolithiums, but are them cesses. Traditional stir-batch modes of synthesis with either selves Volatile and flammable, adding further hazards associ of these types of compounds generate significant quantities of ated with the use of organolithium reagents. Solvent waste, which is undesirable for any chemical process, 0005 Lithium amide, as used herein, refers to lithium salts A cleaner process, which would involve either a solvent-free of primary and secondary amines. Lithiumamide reagents are organolithium or lithium amide material or a packed-bed flow synthetically useful because they are strong bases, freely reactor setup, would be ideal for large scale industrial Syn soluble in common organic solvents, and highly versatile. thesis, as it would decrease solvent disposal issues and might These reagents are, however, very reactive and difficult to eliminate tedious purification or work-up steps. One solution handle. With some exceptions, they are not available com would be the creation of a solid source of organolithium mercially and must be synthesized immediately prior to their reagents which could be used in flow chemistry and would use by adding a primary or secondary amine to an organo control the efficiency and effectiveness of the reagent in a lithium reagent, such as butyllithium. process. This notion has spawned efforts to develop crystal 0006 Lithium metal is commonly used to generate an line Grignard reagents (Marcus, V., et. al. Angew Chem. Int. organolithium reagent, which is an organometallic compound Ed. 2000, 39, 3435) and other solid carbanion sources with a direct bond between a carbonandalithiumatom. Since (Davies, S. G. et al. J. Am. Chem. Soc. 1977, 4, 135 and the electropositive nature of lithium places most of the charge Eaborn, C., et. al. J. Am. Chem. Soc. 1994, 116, 12071) in density of the bond on the carbon atom, a carbanion species is recent years. However, the methods of preparation of these created. This enables organolithium reagents to act as crystalline reagents are typically tedious and specialized for extremely powerful bases and nucleophiles. Typically, orga specific carbanion systems, limiting their utility in large-scale nolithium reagents are synthesized commercially by the reac applications and their applicability as general carbanion tion of a haloorganic with lithium metal, according to R-X- Sources.
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