(12) Patent Application Publication (10) Pub. No.: US 2014/0306153 A1 LEFENFELD Et Al

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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. Patent Application Publication Oct. 16, 2014 Sheet 1 of 11 US 2014/0306153 A1

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LITHIUM-POROUS METAL OXDE al. and U.S. Patent Application Publication No. 200600493.79 COMPOSITIONS AND LITHIUM by Emmel et al). A side reaction that occurs during this REAGENT-POROUS METAL COMPOSITIONS synthesis, especially with alkyl iodides, is the Wurtz reaction, where the R group couples with itself. 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. Grignard reagents, the broadest class of carbanion 2Li->R-Li+LiX (See U.S. Pat. No. 5,523,447 by Weiss et donors, furthermore undergo the Schlenk equilibrium US 2014/03 06153 A1 Oct. 16, 2014 between two equivalents of an alkyl oraryl magnesium halide ment of a primary or secondary amine with an organolithium (2 RMgX) and one equivalent each of the dialkyl- or diaryl reagent. Thus, lithium amide use Suffers from many of the magnesium compound (RMgR) and the magnesium halide same limitations as the organolithium reagents from which salt (Mgxi). This disproportionation reaction multiplies the they are typically derived. The three most common organo reactive species present, and is a sometimes problematic lithium reagents used for generating lithium amides are meth complication, in their applications as carbanion sources. ylithium, butyllithium, and phenylithium, which produce 0009. Only a few of the known organolithium compounds, methane, butane, and benzene respectively during the reac such as butyllithium, methyllithium, and phenylithium, are tion. All of these byproducts pose drawbacks in a manufac commercially available. Many organolithiums that are not turing environment since they are all volatile, flammable commercially available must be prepared from metal-halo materials. Methane and butane are flammable gases at room gen exchange reactions (for a general reference, see Wake temperature and their generation as Stoichiometric byprod field, B. Organolithium Methods, Academic Press; London, ucts in large scale manufacturing is problematic and costly. 1988) that use one organolithium reagent and an organic Benzene is toxic and a known carcinogen. halide in an exchange reaction. Alternatively, pure lithium 0012. A need exists, therefore, to have organolithium and metal and an organic halide can be reacted to form an orga lithium amide reagents available in a dry form that may be nolithium. These transformations represent equilibrium reac easily handled, stored, and used without a significant loss of tions between organic halides, lithium metal, lithium halides their reactivity. This invention answers that need. and organolithium compounds. Synthesizing a clean organo lithium product is difficult since there is often contamination SUMMARY OF INVENTION with unreacted organic halides, which adds hardship to any large scale process development. Lithiation can also be per 0013. In one embodiment, this invention relates to lithium formed by deprotonation reactions or by reductive cleavage metal/porous metal oxide compositions. These lithium metal of ethers and thioethers (Schlosser, M. Organometallics in compositions are prepared by mixing liquid lithium metal Synthesis, Wiley and Sons; Chichester, 1994,47), the Shapiro with a porous metal oxide in an inert atmosphere under exo method (Shapiro, R. H. Org. React. 1976, 23,405), or arene thermic conditions sufficient to absorb the liquid lithium catalyzed lithiation (Yus, M.; Ramon, D. J.; J. Chem. Soc., metal into the porous metal oxide pores. The lithium metal/ Chem. Commun. 1991,398). These methods begin by utiliz porous metal oxide compositions of the invention are prefer ing organolithium itself functioning as a base, and therefore ably loaded with lithium metal up to about 40% by weight, they are not atom-economic from a synthetic standpoint. The with about 20% to 40% by weight being the most preferred approach of directly reacting lithium metal with the haloge loading. nated form of the target organic group is strongly avoided in 0014 Inanother embodiment, this invention also relates to most industries because of the high reactivity and pyrophoric lithium reagent-porous metal oxide compositions having RLi nature of finely divided Li metal. Dispersed lithium prepared absorbed into a porous oxide. In formula RLi, R is an alkyl in a refluxing hydrocarbon also causes hardship in large scale group, an alkenyl group, an alkynyl group, an aryl group, an ups (Joshi, D. K. Sutton, J. W.; Carver, S.; Blanchard, J. P. alkaryl group, or an NR'R' group; R' is an alkyl group, an Org. Process Res. Dev. 2005: 9 (6): 997-1002.). Alterna alkenyl group, an alkynyl group, an aryl group, an alkaryl tively, mercury-lithium (Schollkopf, U.; Gerhart, F. Angew. group; and R is hydrogen, an alkyl group, an alkenyl group, Chem. Int. Ed. Engl. 1981, 20, 795), tellurium lithium an alkynyl group, an aryl group, an alkaryl group. (Shiner, C. S.; Berks, A. H.; Fisher, A. M.J. Am. Chem. Soc. 0015. Accordingly this invention also relates to methods 1988, 110,957. Hiiro, T.; Mogami, T.: Kambe, N.; Fujiwara, for creating new compositions of lithium, organolithium, and S-L: Sonoda, N. Synth. Commun. 1990, 20, 703) and tin lithium amide species formed and stored inside porous metal lithium (Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. oxides, like alumina (Al-O, alumina gel). Lithium absorbed Helv. Chem. Acta 1996, 79, 346) mediated transmetallations into porous Al-O can be used to prepare and form organo are also possible, but mercury, tellurium and tin compounds lithium and lithium amide compounds inside the pores, as are generally toxic, making these reagents unsuitable for well as for in situ generation of carbanions for nucleophilic large scale industrial processes. addition and polymerizations. Pre-made organolithium com 0010. In a different strategy from the present invention, pounds can also be absorbed into the pores of solid inorganic alkyllithiums (Meli, EtLi) are stabilized by adsorbing the Supports. Such as silica or aluminagel, enabling their solvent alkyl lithium onto the Surface of a nonporous inorganic Sup free storage and delivery for use in synthetic transformations. port, such as SiO, CaO, or Al-O, and then coated with a These new compositions are solid-state free-flowing powders paraffin wax (Deberitz et al. U.S. Pat. No. 5,149,889). How that are suitable for use in both batch and flow reactors. ever, in this case, one has to use pre-made alkyllithium reagents. Then, to activate the reactivity, the user must BRIEF DESCRIPTION OF THE DRAWINGS remove the oil, wax, or hydrocarbon, which can add another undesirable separation step. An additional major difference 0016 FIGS. 1A-1C shows spectra representative of the from the current invention is the fact that the alkyllithium is results of Example 3. adsorbed onto the Surface of the inorganic Support, not 0017 FIG. 2 shows a "H NMR spectrum representative of absorbed into the Support. This strategy highlights the chemi the results of Example 4. cal industry’s need and desire for stabilized and easily use 0018 FIGS. 3A-3C show H NMR, CNMR, and ESI able alkyllithium reagents. MS spectra representative of the results of Example 7. 0011 Like organolithium compounds, lithium amides 0019 FIG. 4 shows an "H NMR spectra representative of have a limited commercial availability. While they can be the results of Example Example 8. prepared with difficulty from lithium and a primary or sec 0020 FIGS. 5A-5C show H NMR, GC-MS, and 'C ondary amine, they are most conveniently prepared by treat NMR spectra representative of the results of Example 9. US 2014/03 06153 A1 Oct. 16, 2014

DETAILED DESCRIPTION OF THE INVENTION 160° C. and about 225°C. The heating may be done over a period of time until all of the lithium metal is absorbed, and 0021. The ability to utilize alkali metals, their equivalents, even overnight. and their derivatives in a convenient form continues to be a need in academia, the chemical industry, and for the hydrogen (0025. The lithium metal is believed to be so finely dis production community. Answering that need, the invention persed inside the alumina gel or other porous metal oxides. relates to absorbing lithium metal into a porous metal oxide. The lithium-alumina gel is capable of reacting almost com The porous metal oxides utilized in the composition invention pletely with nitrogen (N) gas. The product of the reaction of are non-reducible porous metal oxides, porous alumina being lithium-alumina gel with nitrogen gas produces finely dis a particularly preferred porous metal oxide. The invention persed lithium nitride (LiN) inside the pores of the alumina. also relates to lithium reagent-porous metal oxide composi The reaction of this LiN with water calmly produces clean tions, organolithium reagents and lithium amides absorbed ammonia gas on demand by the following reaction (where AG into a porous metal oxide. These lithium reagent-porous signifies alumina gel): metal oxide compositions provide a greater variety of acces sible nucleophiles and possess significant advantages in han This material, therefore, produces ammonia by a method that dling and storage over currently known lithium reagents. avoids the hazards of its transportation, transfer, and storage. This pure ammonia can be used for many applications includ Lithium Metal-Porous Metal Oxide Compositions ing, but not limited to, the treatment of stack gases containing 0022. Lithium, the chemical element with the symbol Li, oxides of nitrogen (NO) from fossil fuel combustion pro is in Group 1 of the periodic table, among the alkali metals. It cesses. The lithium-porous metal oxide compositions of the is the lightest of all metals and has a density of only half that invention may, accordingly, be used to Scrub nitrogen gas of water. Lithium is a soft, silvery metal that has a single from inert environments. valence electron, which it readily loses to become a positive 0026. The lithium, metal-porous metal oxide composition ion. Because of this, lithium is flammable and reactive when of the invention is preferably loaded with lithium metal up to exposed to oxygen or nitrogen, and especially water. Accord about 40% by weight, with about 10% to 20% by weight ingly, the metal should be stored in a non-reactive atmosphere being the most preferred loading. or in a non-reactive liquid. Such as a hydrocarbon or naphtha. 0027. The porous metal oxides which may be used may be Though in Group 1, lithium also exhibits some properties of any metal oxide that is not reduced by the lithium metal. The the alkaline-earth metals in Group 2. porous metal oxide powder used in this invention that is most 0023. In preparing the lithium-porous metal oxide com preferable is porous alumina (also referred to as alumina gel. positions, lithium metal is preferably mixed with a porous particularly Y-alumina gel). Other porous metal oxide pow metal oxide (e.g. porous alumina gel) and then heated until ders that may be used for this invention are any transition the lithium metal melts and is absorbed into the metal oxide metal oxide that is not reduced by the lithium metal, such as pores. One method to accomplish this is heating the lithium porous titanium oxide (i.e. TiO, TiO, TiO, TiOs), porous metal in an inert atmosphere. Such as argon or helium, prior to calcium oxide (CaO), porous Zirconia (i.e. ZrO2), porous iron mixing it with a porous metal oxide. Alternatively, the lithium oxide (i.e. Fe2O, or FeO4), porous Co-O, porous metal metal may be mixed as a solid with the porous alumina and the phosphate (MFO), porous hybrid phosphosilicate, porous mixture heated to melt the lithium metal. The heat treatment aluminates, porous alumino silicates, porous vanadates, to absorb the lithium metal can range from 160-325° C. molybdates, etc. Silica gel can only be used to absorb pre preferably between 160-225° C. Another possible way to made Solvated organolithium reagents due to the high reac introduce the lithium metal into the porous alumina is from tivity between silica and neat lithium metal. Given their the vapor phase as done with zeolites (See A. S. Ichimura, J. porous nature, these porous metal oxides can take up large L. Dye, M. A. Camblor and L. A. Villaescusa, J. Am. Chem. amounts of absorbed material. The composition of this inven Soc., 124, 1170-1171 (2002) and D. P. Wernette, A. S. tion has the lithium metal absorbed inside the pores of the Ichimura, S.A. Urbin and J. L. Dye, Chem. Mater. 15, 144 oxide along with the created carbanion or amide species. 1448, (2003)). In another possible method, the lithium metal Porous alumina can be purchased from many companies, could be deposited into the porous alumina from a metal such as W.R. Grace & Co, or Almatis AC. ammonia solution (See M. Makesya and K. Grala, Syn. Lett. 0028. The porous metal oxides used in the porous metal 1997, pp. 267-268). oxide compositions of the invention, preferably have average 0024. A lithium porous metal oxide composition, such as pore sizes ranging from 30A to 500 A. More preferably, the the preferred lithium-alumina gel (Li-AG), may be prepared average pore size may range from 60 A to 190 A. directly heating a mixture of bulk, or shaved, lithium metal 0029. Although porous metal oxides, when purchased, are with the calcined porous metal oxide, e.g. alumina, to form free-flowing powders, they typically contain gaseous mate loose black powders that retain much of the reducing ability rial, such as water and air. These are preferably removed prior of the parent metals. This reaction preferably occurs in an to mixing the porous oxide powders with lithium metal to inert atmosphere, such as in argon or helium. It is believed the form compositions of the invention. The porous metal oxide lithium-porous metal oxide compositions have Small clusters may be de-gassed, using methods known in the art. For of neutral lithium metal absorbed in the porous metal oxide example, to remove the gaseous material the porous metal, pores as well as possibly ionized lithium metal (Li) located oxide may be heated under vacuum in an evacuable flask, first at the walls of the pores with the electron delocalized from the with a hot air dryer and then with a torch. Such heating atom. The materials are pyrophoric, but less reactive in air achieves temperatures of approximately 300° C. It is also than finely divided neat lithium metal. The heating of the possible, and is actually preferred, to remove the gases more lithium metal with the porous alumina gel occurs between easily and to passivate active sites by heating the porous metal about 160° C. and about 325° C., preferably between about oxide to 600° C. or hotter (~900° C.) in air (calcination). The US 2014/03 06153 A1 Oct. 16, 2014 porous metal oxide is typically cooled to room temperature in 0033 Preferred alkyl groups are methyl, ethyl, n-propyl, a dry (and preferably inert) atmosphere before preparing a isopropyl. n-butyl, t-butyl, isobutyl, sec-butyl, cyclopropyl. composition of the invention. cyclobutyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylm ethyl, homologs and isomers of, for example, n-pentyl, Lithium Reagent-Porous Metal Oxide Compositions n-hexyl, n-heptyl, n-octyl, and the like. Preferred alkenyl groups include ethenyl, allyl, and isomers ofbutenyl, pente 0030 This invention also relates to lithium reagent-porous nyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl cyclopro metal oxide compositions having RLi absorbed into a porous penyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclo metal or non-metal oxide. Informula RLi, R is an alkyl group, hexenyl, cyclohepentenyl, cycloeptadienyl, cyclooctenyl, an alkenyl group, an alkynyl group, an aryl group, an alkaryl cyclooctadienyl, and the like. Preferred alkenyl groups group, or an NR'R' group; R is an alkyl group, an alkenyl include acetylenyland isomers ofbutynyl, pentynyl, hexynyl, group, an alkynyl group, an aryl group, an alkaryl group, an heptynyl, octynyl, nonynyl, decynyl. Preferred aryl and XR group (where X can be a heteroatom such, as, for alkaryl groups are phenyl, benzyl, and isomers of tolyl, ani example. Si, S, Sn, Ge, P, and n is an integer), or a Si(R) Syl, analinyl, naphthyl, indenyl, anthryl, pyrrolyl pyridyl, group; R is hydrogen, an alkyl group, an alkenyl group, an pyrimidyl, imidaxolyl pyrazinyl, oxazolyl, isoxazolyl, thia alkynyl group, an aryl group, an alkaryl group, or an Si(R) Zolyl, furyl, thienyl, imidazoyl pyrazoyl, thiophene, N-alky group; and R is an alkyl group, an alkenyl group, an alkynyl lated pyrole, C.-alkylated pyridine, indolyl, quinolinyl, iso group, an aryl group, an alkaryl group. The lithium reagent quinolinyl and the like. porous metal oxide compositions may be prepared by react 0034. When RLi is R. RNLi, the primary or secondary ing a lithium metal-porous metal oxide composition with an amines used to form the Li amide-alumina gel composition, organo halide, RX; by the in situ combination of lithium include, but are not limited to, alkylamines, dialkylamines, metal, a porous metal oxide, and an organo halide, RX; by alkylarylamine, and diarylamines, as well as cyclic secondary absorption of a lithium reagent, RLi, into a porous metal amines. The organic groups bound to nitrogen in these amines oxide; or by reacting a lithium metal-porous oxide composi or for Rin the silyl group Si(R) can include those described tion with a primary or secondary amine, HNR'R''. The groups above for R. Preferred alkyl groups are preferably methyl, R, R, R and R may be further substituted with functional ethyl, n-propyl, isopropyl. n-butyl, trimethylsilyl, triethylsi groups or contain heteroatoms such as N, O, S. etc. which do lyl, t-butyl, isobutyl, sec-butyl, homologs, and isomers of for not react with the lithium in such a way as to prevent the example, n-pentyl, n-hexyl, n-heptyl. n-octyl, and the like. formation of a lithium reagent-porous metal oxide composi Preferred aryl and alkaryl groups are phenyl, benzyl, and tion of the invention. Preferred and exemplary embodiments isomers of tolyl, anisyl, analinyl, naphthyl, indenyl, anthryl. for R, R', Rand Rare described below. Preferred cyclic secondary amines are pyrrolidine, piperi 0031. To prepare a lithium reagent-porous metal oxide dine, and 2.2.5.5-tetramethylpiperidine. composition of the invention, the Li-porous metal oxide com 0035 Any inert solvent which does not react with the position, prepared as described above, may be cooled in a lithium may be used in the preparation of the lithium reagent reaction vessel between about 0°C. and about -78°C. Then compositions of the invention. For example, non-reactive a haloorganic compound, or when R=R'R''N, a primary or hydrocarbons such as hexanes or heptane or a non-reactive secondary amine, (both within RX), is slowly added to the ether such as THF may be used. THF is generally preferred. Li-porous metal oxide, either neator in a solvent. The haloor Highly polar solvents may unfavorably compete with the ganic or amine moves into the pores, and reacts with the reagent RX when forming the lithium reagents-porous metal lithium metal to create the organolithium compound inside oxide compositions. the pores of the metal oxide. After the reaction is heated to 0036) Another method to generate orgnaolithium-porous room temperature, any excess haloorganic, amine, and/or metal oxide compositions of the invention is via a carbon solvent is distilled off to complete the formation of a dry, hydrogen activation, meaning that the organolithium-alu free-flowing powder of a Li reagent-porous metal oxide com mina gel performs a deprotonation of a carbon atom of an position. As shown in Example 8 below organolithium-po added reagent to generate a new carbanion species. This rous metal oxide compositions may also be prepared by the organolithium exchange is typically performed at cold tem reductive cleavage of carbon-heteroatom bond Such as vinyl peratures (e.g. about 23°C. to about -80° C.). Once the new lithium from ethyl vinyl ether. organolithium reagent is formed, it can then be used as a 0032. When the lithium reagent is an organo-lithium com nucleophile or base in a Subsequent reaction with available pound, the haloorganic compounds, RX, that may be used substrates. This reaction can be performed either in a batch or include, but are not limited to, alkyl halides, alkenyl halides flow reactor setup. arylhalides, and alkaryl halides. Preferred halogens are chlo 0037 Yet another method to generate organolithium-po ride, bromide, and iodide. The alkyl, alkenyl, and alkynyl rous metal oxide compositions of the invention is to perform groups may be straight or branched chains as well as cyclic an in situ metal-halogen (metal-element) exchange to trans and heterocyclic alkyl, alkenyl or alkynyl groups. The aryl form one organolithium-porous metal oxide to a second orga and alkaryl groups can be heteroaryl and alk-heteroaryl nolithium-porous metal oxide. A single reaction vessel, either groups. The alkyl groups may preferably a CC alkyl or a Cs batch or flow, is charged with a haloorganic compound, RX, to C cycloalkyl group. The alkenyl groups may preferably a or any activated species with a C-Z bond (where Z can be any C-C alkenyl or a C to C2 cycloalkenyl group. The alkynyl halide or an acidic hydrogen, etc.), can first be dissolved in groups may preferably a C-C alkynyl or a C to C THF at cold temperatures and then have organolithium-po cycloalkynyl group. The aryl and alkaryl groups can be het rous metal oxide added to the vessel. After the cold (i.e. eroaryl and alk-heteroaryl groups. The “alk’ portion of the between about 23°C. and about -80°C.) slurry has been well alkaryl group may be an alkyl, an alkenyl, oran alkynyl group mixed for a time, the organolithium is available to react in the as described here. conventional manner with Subsequently added reagents. US 2014/03 06153 A1 Oct. 16, 2014

0038. The organolithium-alumina gel may also be pre e.g. the corresponding organolithium-alumina gel or lithium pared by an in situ reaction using cut pieces of lithium, porous amide-alumina gel composition. As a more specific example alumina gel, and alkyl halide Solution (preferably, for of the preparation of Such a corresponding composition, the example, hydrocarbon or ether), and evaporating off the Sol lithium-alumina gel is cooled to temperatures ranging from Vent. about -80° C. to about 0°C. and stirred for several minutes. 0039. The organolithium reagent-porous metal oxide To the stirring lithium-aluminagel, a haloorganic, either in its compositions of the invention may also be prepared by the neat form or in Solution of a non-reactive hydrocarbon or absorption of a pre-made organolithium species in a solvent ether solvent such as tetrahydrofuran (THF), is slowly added. into the pores of silica gel or alumina gel under cold condi The reaction mixture is stirred for several hours at cold tem tions. The excess solvent is then distilled away and the pow peratures. Any excess unreacted haloorganic, or solvent, may der is vacuum dried. The product is non-pyrophoric and is be distilled offunder vacuum while the system temperature is preferably referred to as organolithium-silica gel or organo raised to room temperature. The strength (reaction equiva lithium-alumina gel. The method absorbs an organolithium lents per gram) of the final organolithium-alumina gel com species into the pores of a porous metal oxide material by position is measured by performing the nucleophilic addition contacting the organolithium species with the porous material to an electrophile in a separate reaction setup. In the case of under cold conditions (e.g. about 23° C. to about -80° C.), butyl bromide, the reaction appears to be: distilling any excess solvent, and drying the resulting orga nolithium material. 0040. The resulting free-flowing powders, organolithium 0044) Using the pure compound densities of LiBr (3.464 porous metal oxide compositions having RLi absorbed into a g/cm) and BuLi (0.67 g/cm), the volume per mole of prod porous metal oxide performs all the reaction types of conven ucts is 25.1 cm for LiBrand 95.5 cm for BuLi for a total of tional organolithium compounds, such as nucleophilic addi 120.6 cm/mole. The void volume in alumina gel (from mer tions to electrophiles, initiation of polymerizations, and base cury porosimetry) is 1.56 cm/g. Assuming that the products catalyzed reactions, among many others. When there is no fit in the pores without increasing the Volume, then for a residual lithium metal in the material, the powder is also sample of alumina gel of mass 8.0 g, there is a maximum of stable under nitrogen. With or without residual lithium, this 12.5 cm of void space. That means that 8.0 g of AG could material has an extended shelflife at room temperature com accommodate 12.5/120.6=0.110 moles of reaction, which pared to commercially available and conventional Solutions would require 1.53 grams of Li. This would correspond to a Li of organolithium compounds that tend to aggregate, react, loading of (1.53/9.53)x100–16.0 wt %. The loading of BuLi and decompose in the Solvents they are stored inside. would then be 0.110/9.53=0.01.15 moles/g lithium-alumina 0041 Another method to generate lithium amide-porous gel or 11.5mmol/g lithium-alumina gel. metal oXode with the invention is to use an organolithium 0045. The maximum loading of the organolithium-alu porous metal oxide to deprotonate a primary or secondary mina gel for two example systems, butyllithium-alumina gel amine. In a single reaction vessel, either batch or flow, a and methyllithium-alumina gel, are shown In Table 1 below primary or secondary amine, preferably dissolved in a sol on the basis of 10 g total weight of lithium-alumna gel used: vent, is charged to a stirring batch of organolithium-porous metal oxide. After the slurry is well mixed and allowed to TABLE 1 react, any excess amine and/or solvent are decanted, removed under vacuum, or distilled at low temperature to complete the Maximum Loadings formation of a dry, free-flowing powder of lithium amide For BuLi: 2Li + BuBr --> BuLi + LiBr porous metal oxide. Loading of Lithium Alumina Gel 15.0% 0042. The lithium amide-porous metal oxide composi Total Available Volume 13.26 cc tions (R=R'RN) (free-flowing powders) perform the reac Volume per Mole of BuLi Produced 95.52 ccimol tions known for conventional lithium amide compounds. Volume per Mole of LiBr Produced 25.12 cc mol Reaction Potential in Alumina (mol) 0.11 moles These reactions include, but are not limited to, deprotonation Amount of Lito Complete Reaction (g) 1.54 g of most common carbon acids including alcohols and carbo Volume of BuLi Produced 10.50 cc nyl compounds (aldehydes and ketones). When there is no Volume of LiBr Produced 2.76 cc residual lithium metal in the material, the powder is also Amount of BuLi in Alumina 10.99 mmol/g of Li-AG stable under nitrogen. With or without residual lithium, the For MeLi: 2Li + Mel --> MeLi + Lil material has an extended shelflife at room temperature com Loading of Lithium Alumina Gel 17.2% pared to commercially available or conventional lithium Total Available Volume 12.92 cc amide compounds that tend to aggregate and decompose Volume per Mole of MeLi Produced 66.67 ccimol Volume per Mole of Lil Produced 38.35 ccimol slowly. Usual methods for making these lithium amides Reaction Potential in Alumina (mol) 0.12 moles involves the reaction of alkyl lithium species with the corre Amount of Lito Complete Reaction (g) 1.72 g sponding amine (e.g., International Patent Application Pub Volume of MeLi Produced 8.20 cc lication No. WO 03033505 by Detlefet. al.), heating a mix Volume of Lil Produced 4.72 cc ture of lithium with an amine above the melting point of the Amount of MeLi in Alumina 12.30 mmol/g of Li-AG metal (Chiu et al., U.S. Pat. No. 5,420,322) or with small amount ofisoprene as an electron carrier (Corella et al., U.S. 0046. The amount of lithium metal loading is dependent Pat. No. 6,169,203). upon the pore size and pore density of the actual porous metal 0043. As discussed above, a lithium-porous metal oxide oxide used. Typically, the lithium metal may be present in the composition, such as a lithium-alumina gel composition, may compositions of the invention up to about 40% by weight. be used as a starting component for the generation of the Preferably, the amount of metal ranges from 20% to 40% by corresponding lithium reagent composition of the invention, weight, if the material is being used for typical reductions and US 2014/03 06153 A1 Oct. 16, 2014

in situ lithiation applications. The preferred loading to gen tertiary amine stabilizers, can be used as additives to help erate organolithium-porous metal oxide and lithium amide stabilize these reagents by virtue of the tertiary nitrogen coor alumina gel compositions ranges from 10% to 20% lithium dination with the lithium cation. Potentially, this ion com by weight. In the lithium-porous metal oxide compositions of plexation expands the effective radios and reduces the elec the invention, loadings above about 40%, by weight can result trophilicity of the lithium cation, isolating it from the in some free metal remaining on the Surface of the porous carbanion portion and thus limiting its capacity for beta metal oxide. hydride abstraction from the alkyl carbanion. This mode of 0047 Various additives known to stabilize organo lithium stabilization is also thought to enhance the carbanion's avail reagents may also be used with the lithium reagent-porous ability for reaction with externally added reagents. metal oxides. These includebutarelimited to stabilizers, such as tetramethyl ethylenediamine (TMEDA), diazabicycloun Use of Lithium- and Lithium Reagent-Porous Metal decane (DBU), sparteine (see Tsumaki et al., U.S. Pat. No. Oxide Compositions 6,024,897), may also be added to further increase the stability of the carbanions in these solids. For example, stabilized 0048. The lithium-porous metal oxide compositions and versions of organolithium species can be made by using tet the lithium reagent-porous metal oxide compositions of the ramethylethylenediamine (TMEDA) as an additive to the invention may be used for the same reactions as is lithium synthesis. Typically, for every two (2) moles of lithium, one metal, organolithium reagents and lithium amide reagents. (1) mole of haloorganic and one (1) mole of TMEDA is used These include, but are not limited to nucleophilic addition to make organolithium-TMEDA-porous metal oxide. The reactions, polymerization reactions, and base-catalyzed reac molecular structure of TMEDA corresponds to one molecule tions. Table 2 provides an exemplary list of Such reactions. of 1,2-diaminoethane alkylated with two methyl groups on The compositions of the invention, however, have the advan each of the two amine nitrogen atoms. TMEDA, or other tage of being free flowing powders and more storage stable. TABLE 2 Reagent Use Reaction example Reference RLi-AG (1) Nucleophilic additions RLi + RCO->RCOLi Wu, G. Huang, M. to carbon centered RLi+ CO-> RCO,Li Chem. Re: 2006, electrophile 106, 2596. (2) Preparation of Walborsky, H. M.: organocuprate or Gilman's Ronman, P. J. Org. reagent Chem., 1978,43, 731 (3) Preparation of RLi+PX->PR + 3LiX organophosphorous, RLi+ RSCN->RSR-- LiCN organosulfur, organoboron, organotin compounds from appropriate electrophiles (4) Preparation of lithium House et al., J. Org. amides such as LDA and Chem., 1978,43, LHMDS 700. (5) Directed ortho-lithiation and Subsequent quenching with electrophiles. (6) Preparation of enolates nBuLi + toluene-> Eisch, J. J. and other deprotonations BnLi + nBuFH Organomet. Synth. (e.g., preparation of other 1981, 2,95. organolithium by Li-H exchange) (7) Initiator for anionic polymerizations (8) Generation of Ylides in Maercker, A. Org. Wittig reaction React. 1965, 14, 270. (9) Generation of carbene Xu, L.; Tao, F.; Yu, T. Tetrahedron Lett. 1985, 26, 4231. (10) Isotopic labelling (e.g., RLi+ DO->RD + LiOD D, T) (11) Shapiro reaction RNLi-AG (1)As non-nucleophilic base Elimination (e.g., 3-H), Lochmann et al., J. Such as LDA sigmatropic carbanion Organometallic rearrangements, Chem, 1979, 123. generation of carbanions, reductive cleavage of ethers, ortholithiations, aldol reactions, anionic polymerizations Li-AG (1) Preparing organolithium RX+ 2Li->LX+ RL Main Group Metals compounds by halogen RSR + Li->RLi+ RSLi in Organic metal exchange or reductive Synthesis by cleavage of C-O, C-S or C-P Tomooka, K. Ito, M. US 2014/03 06153 A1 Oct. 16, 2014

TABLE 2-continued Reagent Use Reaction example Reference bonds. 2005, Wiley Verlag, GmbH (2) Reductions of cabonyls, RCO -> RCHOH aromatics (Birch reduction) (3) Generation of reactive intermediates Such as arenides,

0049 Additionally, as solid state reagents, the lithium amide formed in situ from the lithium-alumina gel is then porous metal oxide compositions and the lithium reagent allowed to react with a solution of substrate, fed in the same porous metal oxide compositions of the invention may be or different solvent, and forming product that is Subsequently used for reaction purposes in several ways. The simplest eluted from the column. This method is thus advantageous in mode is a conventional batch reaction in which the solid terms of (a) efficient usage of the lithium's reactivity, (b) reagent is stirred in a slurry with a solution of Substrate(s). safety, since the eluted product is free of lithium metal, (c) in Here, the principle advantages over commercially available applications that call for the intermediacy of unstable orga Solid lithium preparations or solutions of organolithium or nolithium species, and (d) in allowing sequential formation lithium amide reagents are in (a) ease of solids handling and and reaction of supported reactants, followed by their elution (b) minimization of organic solvent usage in reaction, from polar/ionic byproducts and unreacted lithium metal. quenching, and workup procedures. In favorable cases, when solid acids are included in the slurry, direct isolation of the EXAMPLES organic solution containing only neutralized product is medi tated by the affinity of the solid oxide gel (e.g., alumina or Example 1 silica) for ionic byproducts which therefore do not have to be removed via separate organic/aqueous partition and washing Preparation of Li-AG (10% w/w) steps. 0050. A second mode of use is in a process flow reactor, 0053 Ina Heglovebox 3.6 g of lithium ribbon (1.425 g/ft) (e.g. a column flow reactor), in which solutions of reaction was weighed out and cut into Small pieces and coated thor substrate percolate through a packed bed of the solid lithium oughly with 28.4 g Alumina gel (AG) before putting into the alumina gel, organolithium-solid oxide, or lithium amide steel reactor. The steel reactor was heated to 100° C. for 6 Solid oxide reagent. With flow process reactors, or continuous hours, 165° C. for overnight, 182° C. for 8 hours and 190° C. flow reactors, fresh reactant Solution is continuously added to for overnight. The steel reactor was cooled and transferred the reactor Solid-state reagent. Reaction products are continu into the glovebox. A small representative sample of 76.7 mg ously removed while the waste is either left bound to the was tested for 1 h evolution with water. The amount of H Supported reagent or co-eluted with desired products. The collected came out to be equivalent to 9.2% of Li. Variations advantages of using a flow process reactor are numerous. For in the amount of lithium loadings have been prepared ranging example, the reactor insures efficient use of all the reagent from 5 wt % to 40 wt.% by varying the stoichiometric ratio of material, only having to be shut down when its reaction lithium metal to porous alumina gel. capacity is fully exhausted. The result is a process both more productive and more efficient in gel material and in Solvent Example 2 than a conventional batch reaction. An example of a flow process reactor is a fixed-bed flow reactor in which a liquid Preparation of Organolithium Species Stabilized Solution of reaction Substrate is percolated through a column Inside Lithium-Alumina Gel of Solid reagent, Such as for example an organolithium-alu mina gel, with direct collection of the product solution at the columns exit. While virtually any type of reaction process and reactor may be used for the reactions described herein, a where RX can be halides (chloride, bromide or iodides) of flow process reactor, such as a fixed-bed flow column reactor, aliphatic (methyl, butyl, etc), aromatic (Phenyl), benzylic, is the preferred reactor type for the reactions of the invention. allylic, homoallylic, propargyllic, sec-alkyl, tertalkyl or neo 0051 Depending on choice of solvent and the nature of the pentyl groups. organic portions, organolithium or lithium amide species 0055 1 g 10% (14 mmole Li) Li in Y-Al-O was taken in a formed via reaction of haloorganic or organic amines with round bottom flask and chilled in a dry ice-acetone bath at lithium-alumina gel may be soluble enough to be eluted, -78°C. followed by dropwise addition of methyl iodide (2 providing flexible access to freshly prepared solutions of pure mL) (neat) into the stirring slurry. The reaction was stirred organolithium or lithium amide reagents. Alternatively, when cold for 2 hours. The excess methyl iodide was distilled off a targeted organolithium species is expected to be particularly after the addition was complete and the mixture reached room unstable or short-lived, its electrophilic partner (e.g. proton temperature. A Small amount of ethane and I was produced Source, ketone, etc.) may be directly included in Solid form in during this preparation, but this Wurtz coupled product could the bed of the packed column, again providing quenched be minimized by maintaining the cold temperature for a neutral product in pure form at the column exit. longer duration. The strength of Melli in alumina was deter 0052 Alternatively, a sequential reaction scheme is pos mined through the nucleophilic addition reaction with excess sible, in which a solid oxide-bound organolithium- or lithium benzophenone. Between various runs, the loading of Melli in US 2014/03 06153 A1 Oct. 16, 2014

alumina (prepared from 10-25% Li in Y-AlO) was deter 0058. The presence of the butyl anion was also confirmed mined to be between 3-7 mmol/g. For stoichiometric reac by running a gas evolution reaction of this material with water tions of organolithium and benzophenone the nucleophilic and analyzing the gas by GC-MS that indicated formation of addition product yield varied between 75%-90% along with butane (MW=58) according to the following reaction. See traces of ortholithiation product. 0056 PhCHLi, n-Bulli, allyllithium and homoallyl FIGS 1A-1B. lithium were prepared using the same procedure and tested for reactivity with enzophenone.

PhCH2Li in alumina OCO

MeLi in alumina

n-Bulli in alumina

allyllithium in alumina

homoallyllithium in alumina

Example 3 Example 4 Preparation of Organolithium-Alumina Gel with Generation of Organo Lithium-Porous Metal Oxide TMEDA Stabilizer Composition and One Pot Nucleophilic Addition to 0057. In a flask containing 2 g of Li-AG (25% Li by Ketone weight) a mixture of 2 g TMEDA, 3 g n-butyl bromide in 20 mL of pentane was distilled in and stirred at -80° C. for 3 0059 hours, followed by a replacement by a dry ice bath at -40°C. and stirring the reaction overnight till it reached room tem perature. The solvents were removed under vacuum to afford a grey free flowing powder. 200 mg of this material was reacted with 1.1 mmole (200 mg) of PhCOPh to afford butyl diphenylalcohol in 60% yield. FIG. 1A shows the 'HNMR of the butyldiphenyl alcohol product. US 2014/03 06153 A1 Oct. 16, 2014

-continued Comparative Example 2 O Attempt to Generate Lithium Dimethylamide from the Reaction of a Secondary Amine with Lithium Metal in the Presence of Alumina Gel 0064. 30 mg of porous alumina gel was combined with 20 HO" mg of finely divided lithium metal in a flask equipped with a vacuum stopper, and to this mixture Me NH was condensed. The reaction vessel was initially kept cool and was then gradually brought to room temperature and was maintained there for 2 h. No coloration of the Me NH or H gas evolution was observed. / Comparative Examples 1 and 2 demonstrate that lithium metal, alone or in the presence of alumina, 0060) 1.5 mmole of homoallylbromide (195 mg) was dis does not form the lithium amide starting from solved in 5 mL dry and distilled THF and this solution was dimethylamine. cooled to -78° C. To this cooled solution 0.5 g of Li in Y-Al-O, (8-12% w/w, 7-10 mmole of Li), was added through Example 6 a solid addition tube for a period of 15 minute. The slurry was stirred for 30 minutes under the same cold condition. To the Continuous Flow Reaction of Organolithium in a cold stirring slurry, 1 mmole of benzophenone (182 mg) Column dissolved in 3 mL THF was added over a period of 15 min utes. The reaction was warmed to room temperature slowly (6 0065 h), followed by quenching with cold water and extraction with EtOAc. The organic layer was evaporated under nitrogen yielding 200 mg (85%) of oily residue. O 0061 FIG.2 shows the "H NMR (8 in ppm) of the product 1H homoallyldiphenyl methyl ketone with peaks as follows: 1. Column with MeLi-AG -e- 7.2-7.8 (m, 10H), 5.8-6.0 (m, 1H), 5.0-5.2 (m, 2H), 2.4-2.6 2. HO" (m. 2H), 2.05-2.15 (m, 2H). OH Example 5 Generation of Organolithium (Lithium Amide) from the Reaction of a Secondary Amine with Lithium in Alumina Gel 0062 1 g of lithium-alumina gel (loaded with 25 wt.% Li) was reacted with dimethyl amine (~4 mL) to afford a deep 0.066 1 mmole (182 mg) of benzophenone dissolved in 5 blue solution at -60° C. Upon gradual warming to room mL of THF was passed through a cold-jacketed column (-40° temperature, the solution mixture began to bubble presum C.) packed with Melli in alumina (5 mM, 2 g) for a period of ably due to formation of hydrogen gas. On standing at room 1 h. The column was washed with excess THF and the col temperature for another 1 h, the blue color of the solution lected product was subjected to quenching in cold water, completely disappeared. Excess unreacted dimethyl amine followed by extraction in EtOAc and evaporation of the was evaporated under vacuum and the resulting Solid was organic layer to afford an oily liquid (185 mg) in 92% crude weighed. 1.35 g MeNLi-alumina gel was obtained (-40% yield (containing traces of ortholithiation product). The pure yield with respect to amount of Li used). alcohol was isolated by reversed phase (Cs) column chro matography by elating with MeOH (73%). Example 7 Comparative Example 1 Attempt to Generate Lithium Dimethylamide from Reduction of a Ketone Using Lithium-Alumina Gel the Reaction of a Secondary Amine with Lithium 0067 Metal 0063 30 mg of fresh and finely divided lithium metal was taken in a round bottom flask equipped with a vacuum stop per, to which Me, NH was condensed. The reaction vessel was initially kept at -60° C. for several minutes and then was Li-AG, H. gradually warmed up to room temperature and maintained at that temperature overnight with a pressure gauge. No colora tion of the Me NH or H gas evolution was observed. US 2014/03 06153 A1 Oct. 16, 2014

-continued -continued OH

0068. 1 mmole (182 mg) of benzophenone dissolved in 5 mL THF was stirred with 0.5g of 12% Li-AG and solid state proton sources such as NHCl, (NH4)HPO, or dropwise Example 9 addition of glacial AcOH at room temperature after a deep blue colored solution is produced. The color of the reaction Preparation of Vinyllithium from Reductive vessel gradually fades and becomes grey at the end indicating Cleavage of Ethylvinylether complete consumption of lithium. The reaction mixture was filtered, the solids washed with hexane, and the solvent was 0072 removed from the combined organic solutions under vacuum to obtain a white Solid corresponding to diphenyl methanol as confirmed by H, C NMR and ESI-MS. See FIGS. 3A-3C. 21\1N21 No + Li-AG > O Example 8

Preparation of RLi-AG from a Three Component Reaction of RX, Lithium Metal, and Alumina Gel E/ + 1 No OH 0069. In a flask containing 2 g of calcined alumina gel and 202 mg of lithium ribbon cut into 5 Small pieces were massed out and equipped with a glass coated magnetic stir bar and a rubber septum. This flask was chilled to -10°C. for 10 min utes in a cryobath. To this flask, 40 mL of dry hexane was added followed by an additional 200 uL of n-BuBr. The (0073 500 mg Li-AG (12% w/w) was weighed out in a reaction was stirred for 30 minutes causing the lithium pieces round bottom flask equipped with a magnetic stirbar and to turn shiny. An additional 500 uL of n-BuBr was added for rubber septum. To this flask, 2 mL ethyl vinyl ether was added the next 1 hr followed by an additional 800 uL of n-BuBrfor via a syringe at -40°C. After stirring the mixture at -40°C. the next 20 minutes. The reaction mixture was stirred in cold for 20 minutes a solution of 1 mmol benzophenone in 3 ml for another 3 hr until all of the lithium and organic derivative ethylvinylether was added to the reaction mixture dropwise. was incorporated into the alumina gel. At this point, the The rate of addition was maintained in Such a way that it was reaction was stopped and maintained cold and the hexane not allowed for the blue color of benzoketyl radical anion to layer was analyzed for n-Bulli. persist (waited till the blue color disappeared after each drop). 0070 212.5 mg of diphenyl acetic acid solution in THF The total addition took about an hour after this time the color was placed in a round bottom flask to which the n-BuLi in of the reaction started to turn red. The reaction was stirred for additional 1 hour in cold and then brought to room tempera hexane layer from the reaction mixture was added. 15.5 mL of ture before quenching with water. The organic layer was hexane Solution was needed to produce a color change of the extracted with ether (multiple times), dried and the crude diphenyl acetic acid, which corresponds to 2 mmol of n-BuLi. yield was recorded to be 200 mg (57%). Based on this finding, the total hexane layer should have 5.16 0074 The 'H NMR (FIG. 5A) of the crude mixture also mmol of n-BuLi making the n-BuLi absorbed in the solid indicates conversion of 54%, and shows "H NMR (8 in ppm) alumina gel should equal 8.84 mmol. peaks as follows: 2.27 (br. 1H), 5.32 (d. 1H), 5.33 (d. 1H), (0071 609 mg of BuLiAG when reacted with 1 mmol of 6.51 (dd. 1H), 7.2-7.5 (m. 10H). PhCOPh (182 mg) afforded nearly 90% conversion of the (0075. The GC-MS (FIG. 5B) indicates formation of desired nucleophilic adduct by 1H NMR, 8 (ppm): 7.2-7.5 nucleophilic adduct corresponding to its m/z, peak at 210. (m. 10H), 2.3 (t, 2H), 1.4 (m, 4H), 0.95 (t,3H). (See FIG. 4). 0.076 °C NMR in: CDC1 (8 in ppm) (FIG.5C) shows peaks at 145.7, 143.5, 128.6, 127.9, 126.9, 114, 79.4 What is claimed is: 1. A method for preparing a lithium reagent-porous metal oxide composition comprising the steps of: 1. nBuLiAG mixing liquid lithium metal with a porous metal oxide in an 2. HO" inert atmosphere under exothermic conditions sufficient to absorb the liquid lithium metal into the porous metal oxide, and US 2014/03 06153 A1 Oct. 16, 2014 11

reacting the resulting lithium metal/porous metal oxide mixing lithium metal, a porous metal oxide, and an alkyl composition with a compound RX at a temperature of halide solution in the presence of a solvent under con about -80° C. to 0°C., ditions sufficient to absorb the lithium into the pores of wherein R is an alkyl group, an alkenyl group, an alkynyl the porous metal oxide, and group, an aryl group, an alkaryl group, or an NR'R' evaporating any excess Solvent. group; 7. The method for preparing an organolithium-porous R" is an alkyl group, an alkenyl group, an alkynyl group, an metal oxide composition of claim 8, wherein the lithium aryl group, an alkaryl group or an Si(R) group; metal is loaded up to about 40% by weight, the pores of the R is hydrogen, an alkyl group, an alkenyl group, an alky porous metal oxide have an average pore size of 30 A to 500 nyl group, an aryl group, an alkaryl group, oran Si(R)s A, and the porous metal oxide is selected from porous alu group; mina, porous titanium oxide, porous calcium oxide, porous R is an alkyl group, an alkenyl group, an alkynyl group, an Zirconia, porous iron oxide, porous Co-O, porous metal aryl group, or an alkaryl group; and phosphate, porous hybrid phospho silicate, porous alumi X is a halogen. nates, porous vanadates, and molybdates. 2. The method for preparing a lithium reagent-porous 8. The method for preparing an organolithium-porous metal oxide composition of claim 1, wherein the lithium metal is loaded up to about 40% by weight, the pores of the metal oxide composition of claim 8, wherein the lithium porous metal oxide have an average pore size of 30 A to 500 metal is loaded to about 20% to 40% by weight. A, and the porous metal oxide is selected from porous alu 9. The method for preparing an organolithium-porous mina, porous titanium oxide, porous calcium oxide, porous metal oxide composition of claim8, wherein the porous metal Zirconia, porous iron oxide, porous Co-O, porous metal oxide is alumina. phosphate, porous hybrid phosphosilicate, porous alumi 10. The method for preparing an organolithium-porous nates, porous vanadates, and molybdates. metal oxide composition of claim 8, wherein the pores of the 3. The method for preparing a lithium reagent-porous porous metal oxide have an average pore size of 80 A to 190 metal oxide composition of claim 1, wherein the lithium A. metal is loaded to about 20% to 40% by weight. 11. A method of absorbing an organolithium species into 4. The method for preparing a lithium reagent-porous the pores of a porous material, comprising: metal oxide composition of claim 1, wherein the porous metal contacting the organolithium species with the porous mate oxide is alumina. rial under cold conditions, wherein the porous material 5. The method for preparing a lithium reagent-porous is selected from the group consisting of porous silica gel metal oxide composition of claim 1, wherein the pores of the and a porous metal oxide, porous metal oxide have an average pore size of 60 A to 190 distilling any excess solvent, and 6. A method for preparing an organolithium-porous metal drying the resulting organolithium material. oxide composition comprising the step of k k k k k