WO2008131270A1 - Method for generating alkali metal phosphides through reduction of tri-substituted phosphines with alkali metal porous oxide compositions - Google Patents

Abstract

Alkali metal phosphides are useful intermediates for the synthesis of a variety of phosphine derivatives. Many of these phosphine derivatives are important industrial compounds with applications as synthetic intermediates or as ligands in a variety of homogeneous and heterogeneous synthetic processes. Alkali metal diarylphosphides in particular have been used in the synthesis of many phosphine ligands of importance. The invention relates to methods for generating and using alkali metal phosphides by reduction of the phosphorus sigma bonds of tri-substituted phosphorus derivatives with Group I metal/porous oxide compositions. Formula (I).

Description

METHOD FOR GENERATING ALKALI METAL PHOSPHIDES THROUGH REDUCTION OF TRI-SUBSTITUTED PHOSPH1NES WITH ALKALI METAL

POROUS OXIDE COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

10001] This application claims priority to U.S. Provisional Patent Application

Serial No. 60/912,557, filed April 18, 2007, which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] This invention relates to the use of Group I metal/porous oxide compositions in the reduction of tri-substituted phosphorus derivatives (PR₃), to generate alkali metal phosphide compounds. The Group I metal/porous oxide compositions used in this invention are easily handled, free flowing solids, which avoid the need for neat alkali metal or liquid ammonia handling or specialized equipment.

BACKGROUND OF THE INVENTION

[0003] Phosphines are widely used in various organic reactions, often as stoichiometric reagents. Due to their ease of preparation, usually from PX₃ (where X is Br, Cl, I, etc.) and ArX, and their relatively little susceptibility towards oxidation in air, triaryl phosphines are the most heavily used phosphines. Some examples of their use are listed below:

• in Wittig reactions to generate ylids by combining phosphonium salts with alkyl halides;

• in Staudinger reactions to generate iminophosphirane intermediates by combining an azide with a phosphine or phosphite;

• in Mitsunobu reactions to generate an inverted chiral secondary alcohol by facilitating the abstraction of O; or

• as ligands for organometalHc catalysts such as the Wilkinson's catalyst (used for hydrogenations), the Heck catalyst (used to form C-C bonds), the Grubbs catalyst, and in (triphenylphosphine)copper hydride hexamers. Important industrial examples of such catalytic reactions where phosphine ligands play a critical role include olefin hydrogenation and hydroformylation.

[0004] Traditional methods of triarylphosphine synthesis include treatment of phosphorus trihalides, such as PCI3 or PBr₃, with a carbon nucleophile such as aryl lithium or aryl magnesium reagents (i.e. Grignard (Ar-MgX) reagents). Trialkylphosphines are traditionally synthesized by hydrophosphination of olefins or reaction of phosphorus trihalides with alkyl lithium or Grignard reagents. These methods suffer several limitations including a relatively small number of suitable precursors for the required lithium or magnesium reagents, the high reactivity of the required reagents, the low temperatures required, and a general lack of selectivity. These limitations are particularly significant for the synthesis of mixed arylphosphines with different aryl groups attached to phosphorus or for mixed alkyl arylphosphines containing both akyl- and aryl- groups attached to the phosphorus.

[0005J One promising and sometimes useful method of synthesis of such mixed phosphines involves the use of alkali metal phosphides and a suitable electrophile. The most common method of employing alkali metal diarylphosphides in synthesis relies on their generation by introducing a triarylphosphine to a mixture of alkali metal in liquid ammonia. These "dissolving metal," or "Birch Reduction," conditions have many difficulties associated with them including the need for special equipment to achieve liquid ammonia handling and recycling, limited temperature ranges for subsequent coupling reactions, poor solubility of many other reagents in liquid ammonia, and poor yields.

[0006] Efforts to avoid the above difficulties have included use of solvents other than liquid ammonia, most commonly tetrahydrofuran or other aprotic solvents, which do not dissolve the alkali metal. Problems commonly encountered under such heterogeneous conditions include variable reaction rates due to particle size effects and metal surface passivation, agglomeration of particles during the course of the reaction, difficulties removing or consuming excess alkali metal, poor reactivity, and low yield.

[0007] Triethyl phosphine has been used in the past to map out the active acidic sites in porous silicas and aluminas (L. Baltusis, et ah, J. Am. Chem. Soc, 1987, 109, 40). The natural affinity of phosphines towards these solid supports displays an obvious advantage for the passage of these phosphine reactants through the alkali metals absorbed in these metal oxide supports.

[0008] Many efforts to optimize the generation and reaction of alkali metal diarylphosphides for a particular application have been made. For example, Pushpananda and Senaratne teach the use of freshly cut sodium in refluxing tetrahydrofuran for the conversion of triphenylphosphine to sodium diphenylphosphide followed by reaction with cycloalkyl electrophiles to form cycloalkyldiphenylphosphines (See US Patent 5,710,340). Layman and Welsh provided and improved the procedure to form these same compounds by reduction of triphenylphosphine with a dispersion of sodium-potassium alloy (e.g NaK) in the presence of hydrogen and subsequent reaction with a cycyloalkyl electrophile {See US Patent 5,866,720, Albemarle). Gandy, Crimins, and Timms teach the use of sodium and sodium dispersions in diamine solvents for the preparation of sodium diarylphosphides (EP 0 973 783Bl, Great Lakes). None of these, however, show the same advantages as displayed in this new methodology.

[0009] Diarylphosphides of alkali metals are valuable organic reagents for accomplishing a multitude of organic transformations such as dehydroxylation of α- hydroxy ketones, stereoselective reduction of organic gem-dihalides, regio and stererospecific cleavage of α,β-epoxysilanes and disilylepoxides, demethylation of methylammonium salts, selective dealkylation of methyl aryl ethers, stereoselective displacements of secondary mesylates and tosylates in steroids, Staudinger reaction, and functionalization of bromouracil, in addition to their other uses in organic syntheses.

[0010] Chiral phosphines are versatile chiral ligands that are widely used in asymmetric synthesis. Common methods of preparation for these chiral phosphines often involve multiple steps and tedious isolations (See U.S. Patent Application Publication Nos. 20040068126, 2003023299, 20050119495, 20050222464, and 20070010695). Diaryl-substituted chiral phosphines are relatively more air stable than their corresponding aliphatic counterparts. These phosphine derivatives can be made via Hg-Pd-mediated couplings (M. A. Bennett, et al, Inorg. Chem., 2002, 41, 844), Zn-based coupling reactions (D. J. Ager, et al, Chem, Comm., 1997, 2359), or from reactions of diphenyl phosphide with the mesyl ester of the respective aromatic compounds (S. Kikuchi, et al, Tetrahedron, 2005, 61, 3587). Other methods are possible as well (K, M. Pietrusiewicz, et al, Chem, Rev., 1994, 94, 1375). [0011] Despite these efforts, there remains a substantial need for a reliable, general, and commercially feasible method for the generation and use of alkali metal phosphides, particularly alkali metal diarylphosphides. The current invention provides a facile, convenient, and high yielding process for the reduction of tri-substituted phosphines to alkali metal phosphides and for their subsequent reaction with electrophiles to generate new phosphine derivatives.

SUMMARY OF INVENTION

[0012] The invention relates to methods of producing phosphine derivatives by combining phosphine compounds with Stage 0 or Stage I Group I metal / porous oxide compositions and electrophiles under suitable reaction conditions to form the desired phosphine derivatives.

[0013] In particular, the invention provides a method of producing a phosphine derivative having the form PR₂R¹ by contacting a phosphine compound, PR3, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately one mole of an electrophile (R¹⁺) under suitable reaction conditions to form the desired phosphine derivative, as represented by the following reaction scheme:

Stage 0 or Stage 1

R _^ ,R GGrroouupp 1I mmeettaall//ppoorrous oxide R_^ R

R Electrophile (R^{1 Θ} ) R^I

wherein R and R^! are independently selected from the group consisting of a halide, an alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain Ci-Cj₈ alkyl, a substituted or unsubstituted, branched or straight chain C₂-C₁8 alkenyl, a substituted or unsubstituted, branched or straight chain C₂-C)_S alkynyl, and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

[0014] The invention also provides a method of producing a phosphine derivative having the form PRR'₂ by contacting a phosphine compound, PR₃, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately two moles of an electrophile (R¹⁺) under suitable reaction conditions to form the desired phosphine derivative, as represented by the following reaction scheme: Stage 0 or Stage I R _{^ ^}R Group i metal/porous oxide p> p>i

R ElectrophiIe (R^{1 @} } RI

wherein R and R¹ are independently selected from the group consisting of a halide, an alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain Ci-C_1S alkyl, a substituted or unsubstituted, branched or straight chain C₂-Ci₈ alkenyl, a substituted or unsbstituted, branched or straight chain C₂-C_1S alkynyl, and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

[0015] The invention also provides a method of producing a phosphine derivative having the form PRR¹R² by contacting a phosphine compound, PR₃, with a Stage 0 or Stage 1 Group I metal / porous oxide composition and approximately one mole of a first electrophile (R¹⁺) under suitable reaction conditions to form a first phosphine derivative, PR₂R¹, as represented by the following reaction scheme:

Stage 0 or Stage t FL -R Group I metal/porous oxide R_^ R

R Eiectrophiie (R¹® ) RI

and subsequently contacting the first phosphine derivative, PR₂R¹, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately one mole of a second electrophile (R²⁺) under suitable reaction conditions to form the desired phosphine derivative, PRR¹R², as represented by the following reaction scheme:

Stage 0 or Stage I R _ ,.R¹ Group i metal/porous oxide R _{V ,,}R¹

R Electrophile (R²®) R2

wherein R, R¹, and R² are independently selected from the group consisting of a halide, an alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain C₁-Ci_S alkyl, a substituted or unsubstituted, branched or straight chain C₂-Cj₈ alkenyl, a substituted or unsubstituted, branched or straight chain C?-Cjg alkynyl,and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle. [0016] In the above reactions, each of R, R¹, and R² may be independently selected from the group consisting of an aryl or heteroaryl, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain C₂-C9 alkenyl, a substituted or unsubstituted, branched or straight chain C₁-C₅ alkyl, a substituted or unsubstituted, branched or straight chain C₂-C₅ alkenyl, and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle. Each of R, R¹, and R² may also be independently selected from the group consisting of a substituted or unsubstituted aryl group including phenyl, tolyl, xylyl, naphthyl, furyl, benzofuranyl, pyranyl, pyrazinyl, thienyl, pyrrolyl, ϊrnidazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indolizinyl, indoazolyl, purinyl, quinolyl, thiazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzothlenyl, anthryl, phenanthtryl, an iso-form thereof, and a substitutional isomer thereof. In addition, R may be independently selected from the group consisting of bromide, chloride, iodide, phenyl, tolyl, xylyl, naphthyl, and benzyl.

[0017] Furthermore, with respect to the Stage 0 or Stage I Group 1 metal / porous oxide composition, the Group I metal may be selected from the group consisting of Li, Na, K, Rb, Cs, and an alloy thereof. The alloy may be selected from the group consisting of NaK, Na₂K, KiNa, and KsNa. In addition, the porous oxide may be selected from the group consisting of silica gel and alumina gel. Also, the Group I metal / porous oxide composition preferably comprises 35-40 wt % of the Group I metal.

[0018] Moreover, the electrophiles (R^{1 +} and R^{2 +}) may be selected from the group consisting of an alkyl halide, an aryl halide, an acyl halides, and an acid anhydrides.

[0019] Thus, as is described herein, the invention relates to the use of Stage 0 and

Stage I Group I metal/porous oxide compositions to reduce phosphorus derivatives (PR3) and generate alkali metal phosphide compounds having various forms. These processes may be performed either in conventional stirred reactors or in continuous flow reactors, where neither process requires specialized equipment for sodium metal or liquid ammonia handling. This invention also relates to methods of generating and using alkali metal phosphides as synthetic intermediates for the productions of various phosphine derivatives.

[0020] For example, the invention provides an improved process for the preparation of alkali metal diakyl- or diarylphosphides comprising the combination of a tri-substituted phosphine (PR3), preferably in an aprotic solvent, with a Group I metal/porous oxide composition, and optionally separating the soluble materials by filtration, decantation, or similar means. The phosphide may be stored in the solution for a reasonable amount of time before separation.

[0021] The invention also provides a method for replacing of a carbon radical species (for example, R, R¹, and R²) of a tri-substituted phosphine with a different radical species by combining a tri-substituted phosphine (PR₃), preferably in an aprotic solvent, with a Group I metal/porous oxide composition, and optionally separating the soluble materials, and combining this mixture with a suitable electrophile, preferably dissolved in an aprotic solvent. Suitable electrophiles include, but are not limited to, alkyl and aryl halides, alkyl and aryl tosylates, and the like.

[0022] In addition, the invention provides a method for sequential replacement of multiple carbon radical species (for example, R, R¹, and R²) of a tri-substituted phosphine comprising the combination of a tri-substituted phosphine (PR3), preferably in an aprotic solvent, with a Group I metal/porous oxide composition, and optionally separating the soluble materials, and sequentially combining this mixture with a suitable electrophile, preferably dissolved in an aprotic solvent. Suitable electrophiles include, but are not limited to, alkyl and aryl halides, alkyl and aryl tosylates, and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure Hs a ³¹P NMR of the reaction described in Example 1.

[0024] Figure 2 is a ³¹P NMR of the reaction described in Example 2.

[0025] Figure 3 is a ³¹P NMR of the reaction described in Example 3.

[0026] Figure 4A is a ³¹P NMR of the reaction described in Example 4.

[0027] Figure 4B is a second ³¹P NMR of the reaction described in Example 4.

[0028] Figure 5A is a ^3SP NMR of the reaction described in Example 5.

[0029] Figure 5B is a GC-MC of the reaction described in Example 5.

[0030] Figure 5C is a second GC-MC of the reaction described in Example 5. (0031] Figure 6 is a ³¹P NMR of the reaction described in Example 6.

[0032] Figure 7 A is a ³ ' P NMR of the reaction described in Example 7.

[0033] Figure 7B is a ¹H NMR of the reaction described in Example 7.

[0034] Figure 7C is a ¹³C NMR of the reaction described in Example 7.

[0035] Figure 8A is a ³¹P NMR of the reaction described in Example 8.

[0036] Figure 8B is a GC-MC of the reaction described in Example 8.

[0037] Figure 8C is a second GC-MC of the reaction described in Example 8.

DETAILED DESCRIPTION OF THE INVENTION

[0038J As described above, the invention relates to a method for reducing tri- substituted phosphorus derivatives (PR₃) to generate alkali metal phosphide compounds with a Stage 0 or I Group I metal/porous oxide composition. The reduced alkali metal phosphide species can then be reacted with an electrophile to generate a new compound. In one embodiment, the invention provides a method for generating an alkali metal phosphide comprises the step of contacting a phosphine with a Stage 0 or Stage 1 Group I metal / porous oxide composition under reaction conditions sufficient to form the corresponding phosphide.

[00391 In particular, the overall methods of reducing tri-substituted phosphorus derivatives of the invention are based on the following double electron attachment reactions, which may be carried out in situ or in separate reactions. For each of the reactions, a slight molar excess of the Group I/porous metal oxide is used to decrease the reaction times. In addition, for the reactions resulting in the formation of phosphorus derivatives having the form PR₂R¹, PRR^ or PRR^R², the electrophiles R^{1 +} or R^{2 +} can be delivered as R¹X or R²X (as an example but not limited to CH₃I, CH₃Br, CH₃Cl, "BuBr, (CHj)₃SiCl, CH₂CHCH₂CH₂Br etc), and may be the same or different. If different electrophiles are used, the reactions may be performed sequentially.

[0040] For reactions resulting in the formation of phosphorus derivatives having the form PR₂R¹: Stage 0 or Stage i R_{^ ^}R Group I metal/porous oxide R R

R Electrophile (R¹® } R1

[004 IJ For reactions resulting in the formation of phosphorus derivatives having the form PRR^! ₂:

Stage 0 or Stage I R _ _^R Group I metat/porous oxide R RI

R Electrophile (R^iθ ) R1

[0042 J For reactions resulting in the formation of phosphorus derivatives having the form PRR¹R²:

Stage 0 or Stage I

R _ _^R¹ Group I metal/porous oxide R R1

P _ ^ ^vp'

R Electrophile (R²® ) R2

[0043] Tri-substituted Phosphines

[0044] Virtually any tri-substituted phosphorus derivatives that do not have other functional groups capable of reacting with the Stage 0 or Stage I Group I metal/porous oxide material may be used with this invention.

{0045] Accordingly, the groups R, R¹, or R² may independently be halide, alkoxide, aryloxide, alkylsulfide, or arylsulfide; substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted, branched or straight chain Ci-Cig alkyl; substituted or unsubstituted, branched or straight chain C₂-C_JS alkenyl; substituted or unsubstituted branched or straight chain C₂-Ci_S alkynyl; substituted or unsubstituted, saturated or unsaturated, carbocycles or heterocycles. Preferably R and R¹ are aryl or heteroaryl; substituted or unsubstituted aryl or heteroaryl; substituted or unsubstituted, branched or straight chain C₂-C₉ alkenyl; -(OCH₂CH₂)^₇-R²; -(OC₃H₆) _I-7-R²; substituted or unsubstituted, branched or straight chain Ci -C₅ alkyl; substituted or unsubstituted, branched or straight chain C₂-C₅ alkenyl; substituted or unsubstituted, saturated or unsaturated, carbocycles or heterocycles;

[0046J More preferably each of R, R¹, or R is, independently, a substituted or unsubstituted aryl group including phenyl, tolyl; xylyl; naphthyl, furyl, benzofuranyl, pyranyl, pyrazinyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indolizinyl, indoazolyl, purinyl, quinolyl, thiazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzothienyl, anthryl, phenanthtryl, and the like, including their corresponding iso-forms and substitutional isomers.

[0047] In some particularly preferred embodiments, R is bromide, chloride, iodide, phenyl, tolyl, xylyl, naphthyl, or benzyl.

(0048] The R, R¹, or R² groups just discussed contemplate that the alkyl, alkenyl, aryl (Ar), carbocycles, and heterocycles may themselves be unsubstituted or substituted. Unsubstituted means the particular moiety carries hydrogen atoms on its constituent atoms, e.g. CH₃ for unsubstituted methyl. Substituted means that the group can carry typical functional groups known in organic chemistry. The alkyl, alkene, and aryl groups, as indicated, may be straight chains or branched structures. For unsaturated moieties, e.g. alkenes, alkynes, unsaturated carbocycles, or unsaturated heterocycles, the degree of unsaturation may vary from one unsaturation to the maximum possible within the particular moiety. Unsaturated groups may also have a mixture of double and triple bonds.

[0049] The same reaction strategy can also be used to create chiral phosphine ligands for asymmetric synthesis or other compounds having multiple phosphine groups. Examples of such ligands include, but are not limited to, the following, which may be prepared from PR3:

iϋ) Ar¹ArP PArAr¹

(iv) R-(+)-Segphos The reactions can be accomplished stepwise using the reactions described above. Alternatively, such compounds can be prepared using divalent electrophilic compounds, e.g. R ²⁺, with the reaction shown below.

Stage 0 or Stage I FU _^R Group 1 metal/porous oxide R _^ p>3

R R 32+ R R

Additional variation may be introduced using further sequential electrophliic reactions according to the invention. R³ is a divalent organic moiety corresponding to those defined for R, R¹, and R², above. For example, R³ may be a divalent substituted or unsubstituted aryl or heteroaryl, a divalent substituted or unsubstituted, branched or straight chain C₁- Ci₈ alkylene, a substituted or unsubstituted, branched or straight chain C₂-CiS alkenylene, a substituted or unsubstituted branched or straight chain C₂-Ci_S alkynyl, and a divalent substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle. [0050] Chiral phosphines derived from diarylphosphine building blocks can be accessed in a variety of different methods that involve either metal salts of diaryl phosphides, monoarylalkylphosphides, diarylphosphines, diarylphosphites, and diarylphosphinehalides. Some example prior art reactions are:

4 Il J + 8NaPRR'-

(RR)-I (SS)-I (RS)-I

J Am Chem Soc 1979, 101, 6254

77-97% Yield J Org Chem 1994, 59, 7180

USP 5399731 , 21 Mar 1995 Organic Syntheses, 1999, 76, 6-11. [00511 Another example of such a reaction would be the Palladium-catalyzed γ arylation of a β ,γ -unsaturated ketone: applied to a one-pot synthesis of a tricyclic indoline, (Hyde, Alan M.; Buchwald, Stephen L Angewandte Chemie, International Edition (2008), 47(1), 177-180).

(32-50% overall Yield, 90-92 % ee)

[0052] Typically, these ligands can be made from the reaction of diphenyl phosphides with the corresponding halo alkyl or arene derivative. Most of these diphenyl phosphines are relatively more air-stable than their aliphatic analogues and, therefore, easier to handle. In some cases, the oxidized diphenylphosphites can also serve as chiral ligands in asymmetric synthesis. Sterically hindered tertiary phosphines can also serve as chiral racemic synthons for asymmetric catalysts where the active chiral catalyst can either be isolated via dynamic kinetic resolution of organometallic complexes of priviledged ligands (e.g., BINOL, VANOL, TADDOL, phosphoramides or their derivatives) or from chiral natural pools (e.g., D-sugar, L-amino acids, cinchonine or their derivatives etc) or generated in the reaction pot.

[0053] Group I Metal/Porous Oxide Compositions

[0054] Group I metals, or alkali metals (Li, Na, K, Rb, Cs), and their alloys, have been known for many years to reduce triarylphosphines to the alkali metal salt of the diarylphosphides with concomitant formation of the alkali metal aryl species. While these transformations can be performed readily in a laboratory environment under controlled condition, handling of alkali metals, or their alloys (i.e. NaK) is problematic in manufacturing environments because of the extremely reactive nature of these species. The metals and their alloys are known to react with air and water causing the combustion of the reaction product of highly flammable hydrogen gas. Furthermore, liquid ammonia is frequently required as a solvent for these transformations which adds additional safety and handling requirements and costs. [0055] Recently, new Group I metal/porous oxide compositions having improved handling and safety characteristics have been described. These new materials have an alkali metal or alkali metal alloy absorbed into porous oxides, such as silica gel and alumina gel. The new materials retain the reactivity of the native metal, while being much less dangerous than the bulk metal. Accordingly, the term "Group I metal/porous oxide composition" as used herein refers to the material that is formed when an alkali metal, or an alkali metal alloy, is absorbed into porous oxide compositions. The Stage 0 or Stage I Group I metal/porous oxide compositions used in the invention may be prepared as disclosed in U.S. Patent Application No. 10/995,327, filed November 24, 2004, now U.S. Patent No. 7,211, 539, and U.S. Patent Application No. 11/232,077, filed September 22, 2005, now U.S. Patent No. 7,259,128, which are hereby incorporated by reference in their entirety.

[0056] As is disclosed In U.S. Patent Nos. 7,211,539 and 7,259,128, given the pyrophoric nature of alkali metals and their alloys, the ability to utilize alkali metals or their equivalents in a convenient form continues to be a need in the chemical industry. However, the stability of alkali metals and alkali metal alloys in air can be dramatically improved by absorbing the alkali metals into porous oxide supports. For example, these metals can be made significantly more stable by absorption into silica gel to form the alkali metal - silica gel materials or into porous alumina powders to form alkali metal - alumina gel materials. The alkali metal - alumina gel materials are more reactive towards air than the silica gel materials. In terms of newer process development this idea was attractive owing to its operational simplicity; as such, solid-state reducing agents could in principle be employed in a fixed, or fluidized, bed flow reactor, potentially replacing the traditional stirred batch mode of doing chemical reactions.

[0057] The preferred Stage 0 and Stage 1 alkali metal / porous oxide compositions include 35-40 wt. % alkali metal or alkali metal alloy in silica gel or alumina gel. For Stage 0, K₅Na, K₂Na, and Na₂K are the preferred metals. For Stage I, Na, K, NaK, Na₂K, K₂Na and K₅Na are the preferred metals. These materials are available from SiGNa Chemistry, LLC, New York, New York.

[0058] Solvents [0059] The solvent for the reactions described herein may be any suitable organic, polar aprotic solvent. Because the Group I metal/porous oxide compositions can react with protons to form H₂ in the reaction, it is necessary that the solvent should not exchange protons easily with the reaction materials. Preferred solvents include, for example, ethers such as tetrahydrofuran (THF) or 1 ,2-dimethoxyethane (DME). It is preferred that the reactions be carried out in an inert gas atmosphere with dry solvents under anhydrous conditions.

10060] Additional suitable solvents include polar aprotic solvents, such as THF, that provide reasonable solubilities of the reactants, intermediates and products, and that will be easy to separate form the reaction products. Additional possibly suitable solvents include, diethylene glycol dimethyl ether, 1 ,4-dioxane, hexamethylphosphoric acid triamide, tetraalkylureas, tetraalkylsulfonamides, etc. Acetonitrile, DMSO, and pyridine may also be suitable solvents depending on the specific reaction conditions. Some solvents, such as alcohols, such as ethanol; chlorocarbons, such as chloroform and dichloromethane; carbonyl species, such as esters and ketones, such as ethyl acetate and acetone, may not be suitable for use as solvents because of the likelihood of producing undesired byproducts during the reaction. However, there may be specific reaction conditions that make one or more of these solvents desirable.

[0061] Electrophiles

[0062] Generally, any electrophile which may add to the phosphorous / Group I metal/porous oxide composition may be used. Suitable electrophiles include, but are not limited to, alkyl halides, aryl halides, acyl halides, and acid anhydrides. Alkyl and aryl halides, or pseudohalides, are identified by R'-X', where X' may be a leaving group, such as F, Cl, Br, I, CN, SO₂Cl, OSO₂R², OPO₃(R²)₂ and R¹ can be CH₃, CH₃CH₂, iPr, secBu, tertBu, iso-Bu, neopentyl, norbornyl, allyl, homoallyl, propargyl, etc.; aryl or heteroaryl, such as CgH₅, ferrocenyl, pyridyl, thiophenyl, furyl, pyrrolyl, indole, etc.; and acyl such as acetyl, benzoyl halide etc. Aldehydes and ketones may also be used, such as formaldehyde, acetaldehyde, propanaldehyde, acetone, benzophenone etc. Acid anhydrides may also be considered, such as acetic anhydride, succinic anhydride etc. as well as tetra-alkyl ammonium, phosphonium halides such as tetrabutyl ammonium bromide, tetrabutyl phosphonium bromide etc. Epoxides, such as ethylene oxide, and other systems such as aziridines and thirane are also considered. [0063] Reaction Chemistry

[0064] Recently, Group I metal/porous oxide compositions have been found to rapidly reduce tri-substituted phosphorus derivatives (PR3) to alkali metal phosphides in tetrahydrofuran (THF) and other related solvents. Surprisingly, and specifically, enabling to the current invention, these new Group I metal/porous oxide compositions have also been found to sequentially reduce one, two, or all three alkyl or aryl substituents from phosphorous depending on the stoichiometry and reaction conditions.

[0065] Suitable Reaction Processes

[0066J The methods of the invention may be carried out using various industrial reaction processes. For example, the reactions of the invention may be carried out in batch or fixed-bed flow reaction conditions, with each having satisfactory results. As will be understood by a person of ordinary skill in the art, batch process reactors are the simplest type of reactor. A batch reaction process consists of filling the reaction vessel with the desired reaction components, and allowing the reaction to proceed, typically with stirring to promote contact and mixing of the reagents under specific desired reaction conditions. At the conclusion of the reaction, the reaction mixture is removed from the reactor and subjected to physical (filtration) and chemical (e.g. solvent evaporation, crystallization, chromatography) separation steps to isolate desired products, and the process may be repeated. With respect to the invention, a batch process may be used to contact the chosen solid Stage 0 or Stage I alkali metal - porous oxide with a halogen, alkyl, aryl, or vinyl phosphine or phosphate solution in the desired solvent, and then allowing the reaction to proceed under conditions sufficient to complete the reaction and form the corresponding alkali metal phosphide. Afterwards, an electrophile maybe added until formation of the product is complete.

[0067] With continuous process reactors, or continuous flow reactors, fresh reaction materials are continuously added to the reactor and the reaction products are continuously removed. As a result, the material being processed continuously receives fresh medium and products and waste products and materials are continuously removed for processing. Advantages of using a continuous process reactor are numerous. For example, the reactor can thus be operated for long periods of time without having to be shut down, thereby resulting in the continuous process reactor being be many times more productive than a batch reactor. An example of a continuous process reactor is a fixed-bed flow reactor in which a liquid solution of reaction substrate is percolated through a column of solid reagent, such as alkali metal - porous oxides, with direct collection of the product solution at the column's exit. For sequential reactions, the electrophile may be present in the receiving vessel. While virtually any type of reaction process and reactor may be used for the reactions described herein, a continuous process reactor, such as a fixed-bed flow column reactor, is the preferred reactor type for the reactions of the invention.

[0068] As is described above, the invention provides that alkali metals and their mixtures in porous oxides can act as efficient reagents for forming the alkali metal phosphide.

[0069] Examples:

[0070] In each of the examples below, 35 wt. % (i.e., 35g of alkali metal or its alloy in 65g of silica gel) Stage I alkali metal - silica gel (reducing power determined by titrating with water) was used unless otherwise specified.

[0071] All spectra were recorded with a Varian 500 MHz or 300 MHz superconducting NMR spectrometer operating at 499.738MHz and 300MHz resρectively,for ¹H nuclei and interfaced with a Sun Microsystem Ultra5 UNIX console system. Sufficiently long delay times (typically 3 s) were used for acquiring spectra). GC- MS were recorded in a Hewlett Packard 5890 Series II gas chromatograph and Trio-1 series 4286 mass spectrometer.

[0072] Example 1 : Generation of n-Butyldiphenylphosphine with Stage I Na-SG

(Sodium-Silica Gel) in THF.

(0073] In a round bottom flask equipped with a glass coated magnetic stir bar and rubber septum, 262 mg of PPI1₃ (lmmol, lequiv.) and 440 mg of Na-SG (6.7 mmol, 3.35 Na equiv.) were added under an inert atmosphere. 20 mL of freshly distilled anhydrous THF was added to the flask, and the reaction was stirred at 40 ⁰C. The reaction mixture turned yellowish orange within an hour. After 8 hrs, an aliquot of this reaction was quenched with excess n-BuBr and a 98% conversion to "BuPPh₂ was indicated by ³¹P NMR, which is shown in Figure 1. (literature reference -17.1ppm with respect to PPh₃ at -4.7ppm ) (R. Bosque, J. Sales, J. Chem, Inf. Comput ScL, 2001, 41, 225) [00741 Example 2: Generation of n-Butyldiphenylphosphine with Stage I Na₂K-

SG in THF

[0075] In a round bottom flask equipped with a glass-coated magnetic stir bar and rubber septum, 261.8 mg of PPI1₃ (Immol, 1 equiv.) and 416 mg of Stage I Na₂K-SG (Na₂. K-Silica Gel) (5.14 mmol, 2.57 equiv.) were added under an inert atmosphere. To this flask, 20 mL of freshly distilled anhydrous THF was added. The reaction was stirred at 45 ⁰C. The reaction color changed from colorless to an intense orange within 1 hr indicating the generation of diphenyl phosphide. 1 mL aliquots were withdrawn after 0.5 h, 1.5 h, 2 h, 2.5 h, 3 h, and 4 h respectively and were quenched inside a NMR tube with 20 μL of 1- bromobutane. ³¹P NMR of the aliquots (Figure 2) indicated conversions of the phosphide to n-butyldiphenylphosphine in the following extents: 39.8% (0.5h), 54.3% (1.5h), 66.4% (2h), 68.2% (2.5h). 75.7% (3h), and 85.5% (4h) respectively.

[0076] Example 3: Generation of n-Butyldiphenylphosphine with Stage I Na₂K-

SG in DME

[0077] In a round bottom flask equipped with a glass-coated stir bar and rubber septum, 262 mg OfPPh₃ (Immol, 1 equiv.) and 400 mg OfNa₂K-SG (4.94 mmol, 2.47 equiv.) were added under an inert atmosphere. To this flask, 20 mL dry 1,2- dimethoxyethane was added via a syringe. The reaction flask was heated to 45-50 ⁰C and maintained under dynamic stirring. 1 mL aliquots of the reaction mixture were withdrawn after 1 h, 2 h, and 3 h respectively and were quenched inside NMR tubes with 20 μL of 1 - bromobutane. ³¹P NMR of these aliquots (Figure 3) indicates conversion of the phosphide to n-butyldiphenylphosphine in the following extents: 73.4% (Ih), 90.8% (2h), 94.1% (3h) respectively.

[0078] Example 4: Generation of n-Butyldiphenylphosphine with Catalytic

Ethylenediamine and n-BuBr Quench

[0079] In a round bottom flask equipped with a glass coated magnetic stir bar and rubber septum, 262 mg OfPPh₃ (lmmol, lequiv.) and 300 mg of Stage I Na-SG (4.56 mmole, 2.28 equivalents) were added inside an inert atmosphere. To this flask, 20 mL of THF was added followed by the addition of 100 μL of ethylenediamine through a syringe while maintaining an inert atmosphere. The reaction was stirred at room temperature. 1 mL aliquots were withdrawn after 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, and 5 h and were quenched inside a NMR tube with 20 μL of 1 -bromobutane. ³¹P NMR of the aliquots (Figures 4A-4B) indicate conversion to n-butyldiphenylphosphine in the following extents: 25.9% (0.5h), 44.1% (Ih), 50.5% (1.5h), 66% (2h), 71.3% (2.5h), 82.7% (3h), 86.7% (3.5h) and 95.2% (5h) respectively.

[0080] Example 5: Generation of Di-p-tolylbutylphosphine (ⁿBu-P(para-tolyl)2) from Tris(p-tolyl)phosphine and "BuBr Quench

[0081] In a round bottom flask, tris(paratolyl)phosphene (304 mg, 1 mmole) and

400 mg of Stage I Na₂K-SG (4.94 mmol, 2.47 equiv) were assembled in an inert atmosphere. To this flask, equipped with a glass-coated magnetic stirrer and a rubber septum, 20 mL 1 ,2-dimethoxyethane (DME) was added and stirred at 70 °C for 1 hr and then at 50 ⁰C for 5.5 hrs. After this period, the stirring was stopped and the reaction mixture was decanted through a glass wool plug to another flask containing 500 mg "BuBr. The orange colored solution faded in color on coming in contact with the ¹⁵BuBr. A white colored solid was obtained on drying the reaction mixture and weighed 290 mg (expected mass 270 mg). GC-MS (Figure 5B-5C) and crude NMR (Figure 5A) of this quenched solution indicated 85% conversion to ⁿBu-P(para-tolyl)₂.

[0082] Example 6: Generation of Diphenyltrimethylsilylphosphine (TMS-PPh₂) from Triphenylphosphine and Trimethylsilylchloride (TMS-Cl) Quench

[0083] In a round bottom flask equipped with a glass-coated stir bar and a rubber septum, 800 mg of Stage I Na₂K-SG (9.88 mmol, 2.47 equiv.) and 524 mg PPh₃ (2 mmol, 1 equiv.) were added followed by the addition of 20 rnL of THF. This mixture was initially stirred at 60 ⁰C for 1 hr then at 45-50 ⁰C for an additional 4 hrs. This reaction led to the generation of PPh₂ ^H. The PPh₂ ^(→ solution was separated from the Na₂K-SG by filtering and washing through glass-wool. A portion of the resulting filtrate, approximately 15mL, was added to a flask containing TMS-Cl (250 mg, 2.3 mmole). ³¹P NMR (Figure 6) of this crude solution showed a new peak at -58.2 ppm, which indicated 80% conversion to the desired product of TMS-PPh₂ (compared with literature value of - 56.8 ppm from J. Org. Chem., 1987, 52, 748).

[0084] Example 7: Generation ofHomoallyldiphenylphosphine from

Triphenylphosphine and a Homoallylbromide Quench

[0085] In a round bottom flask equipped with a glass-coated stir bar and a rubber septum, 400 mg of Stage I Na₂K-SG (4.94 mmol, 2.47 equiv.) and 262 mg PPh₃ (1 mmol, 1 equiv.) were added followed by the addition of 20 mL of 1 ,2 dimethoxyethane (DME). This mixture was stirred at 45-50 ⁰C for 7 hrs to generate the diphenylphosphide. The PPh₂ ⁽ ' solution was separated from the Na₂K-SG by filtering and washing with an additional 10 mL of DME and then quenched with 270 mg of homoallylbromide (2 mmol). The solution turned from orange to colorless and was then dried yielding 210 mg (88% yield) of crude white solid. ³¹P NMR (Figure 7A) of this material showed a new peak at -15 ppm, along with ¹H (Figure 7B) and ¹³C NMR (Figure 7C) indicating homoallyldiphenylphosphine production. [0086] Example 8: Generation of Phenylmethylbutylphosphine from

Methyldiphenylphosphine and °Butylbromide Quench

[0087J In a round bottom flask equipped with a glass coated stirrer and a rubber septum Na₂K-SG(I) (420 mg, 5.04 mmole, 2.52 equiv.) was weighed out in inert atmosphere. To this flask a 5 mL solution of PPl^Me (200 mg, 1 mmol, 1 equiv.) in THF was added under inert atmosphere and stirred at room temperature for Ih. After this time, stirring was stopped and a 200 μL reaction aliquot was withdrawn via a syringe and added in a NMR tube containing 50 μL ¹¹BuBr in 1 mL toluene. The resulting ³ⁱP NMR (Figure 8A) of reaction aliquot indicated 94.5% conversion to tertiary phosphine "BuMePhP. The identity of this new species was confirmed by GC-MS (m/z at 180 being the molecular ion peak) (Figures 8B-8C).

Claims

The claimed invention is:

1. A method of producing a phosphine derivative, comprising the step of: contacting a phosphine compound, PR₃, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately one mole of an electrophile (R¹⁺) under suitable reaction conditions to form a phosphine derivative, PR₂R¹, as represented by the following reaction scheme:

Stage 0 or Stage I R-_. .,R Group I metal/porous oxide R_^ R

R Eiectrophiie (R¹® ) RI

wherein R and R¹ are independently selected from the group consisting of a halide, an alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain Ci-Cis alkyl, a substituted or unsubstituted, branched or straight chain C₂-Cig alkenyl; a substituted or unsubstituted branched or straight chain C₂-C₁₈ alkynyl; and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

2. A method of producing a phosphine derivative, comprising the step of: contacting a phosphine compound, PR₃, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately two mole of an electrophile (R¹⁺) under suitable reaction conditions to form a phosphine derivative, PRR^, as represented by the following reaction scheme:

wherein R and R^! are independently selected from the group consisting of a halide, art alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain Q-Cig alkyl, a substituted or unsubstituted, branched or straight chain C₂-C_{J S} alkenyl; a substituted or un substituted, branched or straight chain C₂-Ci₈ alkynyl; and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

3. A method of producing a phospMne derivative, comprising the steps of: contacting a phosphine compound, PR₃, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately one mole of a first electrophile (R¹⁺) under suitable reaction conditions to form a first phosphine derivative, PR₂R¹, as represented by the following reaction scheme:

Stage 0 or Stage I R . _^R Group I metal/porous oxide R R

R E!ectrophile (R^iΘ) RI and

contacting the first phosphine derivative, PR2R¹, with a Stage 0 or Stage I Group I metal / porous oxide and approximately one mole of a second electrophile (R²⁺) under suitable reaction conditions to form a second phosphine derivative, PRR R², as represented by the following reaction scheme:

Stage 0 or Stage I R_{v ^}R¹ Group I metal/porous oxide R_^ RI

R Electrophile (R^2Θ ) R2

wherein R, R¹, and R² are independently selected from the group consisting of ahalide, an alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain Ci-C_1g alkyl, a substituted or unsubstituted, branched or straight chain C₂-C₁8 alkenyl; a substituted or un substituted, branched or straight chain C₂-C_]S alkynyl; and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

4. The method of any one of claims 1 to 2 wherein each R and R is independently selected from the group consisting of an aryl or heteroaryl, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain C₂-C₉ alkenyl, a substituted or unsubstituted, branched or straight chain C]-C₅ alkyl, a substituted or unsubstituted, branched or straight chain C₂-C5 alkenyl, and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

5. The method of claim 3 wherein each R, R¹, and R is independently selected from the group consisting of an aryl or heteroaryl, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain C₂-C9 alkenyl, a substituted or unsubstituted, branched or straight chain Cj-C₅ alkyl, a substituted or unsubstituted, branched or straight chain C₂-C₅ alkenyl, and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

6. The method of any one of claims 1 to 2 wherein each R and R is independently selected from the group consisting of a substituted or unsubstituted aryl group including phenyl, tolyl, xylyl, naphthyl, furyl, benzofuranyl, pyranyl, pyrazinyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indolizinyl, indoazolyl, purinyl, quinolyl, thiazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzothienyl, anthryl, phenanthtryl, an iso-form thereof, and a substitutional isomer thereof.

7. The method of claim 3 wherein each R, R¹, and R² is independently selected from the group consisting of a substituted or unsubstituted aryl group including phenyl, tolyl, xylyl, naphthyl, fttryl, benzofuranyl, pyranyl, pyrazinyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indolizinyl, indoazolyl, purinyl, quinolyl, thiazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzothienyl, anthryl, phenanthtryl, an iso-form thereof, and a substitutional isomer thereof.

8. The method of any one of claims 1 to 3 wherein each R is independently selected from the group consisting of bromide, chloride, iodide, phenyl, tolyl, xylyl, naphthyl, and benzyl.

9. The method of any one of claims 1 to 3 wherein the Group I metal is selected from the group consisting of Li, Na, K, Rb, Cs, and an alloy thereof.

10. The method of claim 9, wherein the alloy is selected from the group consisting of NaK, Na₂K, K₂Na, and K₅Na.

11. The method of any one of claims 1 to 3 wherein the porous oxide is selected from the group consisting of silica gel and alumina gel.

12. The method of any one of claims 1 to 3 wherein the Group I metal / porous oxide composition comprises 35-40 wt % of the Group I metal.

13. The method of any one of claims 1 to 2, wherein the electrophile (R^{1 +}) is selected from the group consisting of an alkyl halide, an aryl halide, an acyl halides, and an acid anhydrides.

14. The method of claim 3, wherein the first electrophile (R^{1 +}) and the second electrophile (R^2τ) are selected from the group consisting of an alkyl halide, an aryl halide, an acyl halides, and an acid anhydrides.

15. A method of producing a phosphine derivative, comprising the step of: contacting a phosphine compound, PR₃, with a Stage 0 or Stage I Group I metal / porous oxide composition and approximately one mole of an electrophile (R³²⁺) under suitable reaction conditions to form a phosphine derivative, R₂PR PR₂ as represented by the following reaction scheme:

Stage 0 or Stage I „ R _{^ ^}R Group I metal/porous oxide R R3 0

2 P ^ ¹^ ^p '¹^ *ηp _'"

R _R32₊ ft R wherein each R is independently selected from the group consisting of a halide, an alkoxide, an aryloxide, an alkylsulfide, an arylsulfide, a substituted or unsubstituted aryl or heteroaryl, a substituted or unsubstituted, branched or straight chain Ci-Cjg alkyl, a substituted or unsubstituted, branched or straight chain C₂-Ci_S alkenyl; a substituted or un substituted, branched or straight chain C₂-Cj_S alkynyl; and a substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle and

R³ may be a divalent substituted or unsubstituted aryl or heteroaryl, a divalent substituted or unsubstituted, branched or straight chain Ci -C ^ alkyl ene, a substituted or unsubstituted, branched or straight chain C₂-Ci_R atkenylene a substituted or un substituted, branched or straight chain C₂-Qg alkynylene; and a divalent substituted or unsubstituted, saturated or unsaturated, carbocycle or heterocycle.

16. A method for generating an alkali metal phosphide comprises the step of: contacting a phosphine with a Stage 0 or Stage 1 Group I metal / porous oxide composition under reaction conditions sufficient to form the corresponding phosphide.