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Several approaches were developed for the preparation of phosphorus-substituted 5- and 6-membered benzophostams. Carbodiimide-promoted cyclization of zwitterionic aminophosphinates derived from a nitrobenzene precursor accomplished the cyclization in good yields. Alternatively, a novel copper-catalyzed cross-coupling between a phosphonamide and a bromobenzene precursor produced the heterocycles in moderate to good yields. Three different methods are compared for the synthesis of the P-ethoxy-substituted 5-membered benzophostam.

Thiophosphorus acids R1R2P(S)OH constitute an important class of organophosphorus compounds, in which the phosphorus atom is intrinsically chiral if R1 ≠ R2. In connection with a project aimed at the preparation of chiral thiophosphorus acids, various available literature methods were considered, but few fit the requirement of odorless reagents. Herein, the results of our studies on the synthesis of thiophosphinic acids are reported. Ultimately, two major approaches were selected: (1) the Stec reaction of phosphorus amides with carbon disulfide; and (2) the one-pot synthesis of thiophosphorus acids from H-phosphinates, an organometallic nucleophile, and quenching with elemental sulfur. An application to the preparation of a potential chiral phosphorus organocatalyst is also reported.

The free-radical arylation of H-phosphinates and related compounds was examined. A practical catalytic process with the air as the oxidant could not be found. However, an inexpensive and robust methodology was developed, using catalytic Mn(II) as the radical initiator and excess Mn(IV) as the stoichiometric oxidant. Using these conditions, the inter- and intramolecular arylation of phosphinylidene compounds has a broad scope, including application to the synthesis of P-heterocycles. A full account of this methodology is presented including a discussion of its limitations.

The cost of reagents and catalysts employed in synthetic methodologies developed in academia is very rarely discussed. Yet these costs are very real as they represent a significant portion of any grant proposal budget. Herein, we wish to introduce the concept of Cost of Academic Methodologies (CAM) as an aspect, which should be considered when evaluating synthetic methodologies. We also introduce an associated concept: the Aggregate Molecular Weight (AMW). In order to illustrate these concepts, examples from various laboratories, including our own, are evaluated through the CAM/AMW lens.

Several major challenges still remain in organophosphorus chemistry. Organophosphorus compounds are currently synthesized from phosphorus trichloride (PCl3), even though the final consumer products (such as pesticides, flame-retardants, extractants) do not contain reactive phosphorus-chlorine bonds. In order to bypass phosphorus trichloride, significant interest has been devoted to functionalizing elemental phosphorus (P4, the precursor to PCl3), red phosphorus (Pred), or phosphine (PH3). Yet, phosphinates (ROP(O)H2) are already available on an industrial scale and are the most environmentally benign, but their use as phosphorus trichloride replacements has been completely overlooked until a few years ago. An overview of some of the methodologies developed in my laboratory for P–C and P–O bond-forming reactions through phosphinate chemistry, as well as some selected applications, are presented. Another significant challenge remains the synthesis of P-stereogenic compounds. My group’s recent progress in this area is also discussed. Based on menthol as an inexpensive chiral auxiliary, various menthyl phosphinates can be synthesized. These phosphinates are precursor to P-stereogenic phosphines through well-established literature transformations.

Carbon-phosphorus (C−P) bond-forming reactions via homolytic aromatic substitution (HAS) of non-functionalized substrates with phosphinylidene P(O)H compounds is becoming a useful synthetic tool for the preparation of aryl and heteroaryl phosphonates, phosphinates, and phosphine oxides. This review specifically covers recent work using manganese-mediated free radical processes. Several research groups employ expensive Mn(OAc)3, whereas our own contributions focus on the novel and inexpensive Mn(OAc)2/MnO2 system.

Easily prepared menthyl phosphinates of high diastereoisomeric purity provide versatile intermediates for the synthesis of P-stereogenic compounds. Previous efforts starting about fifty years ago have been hampered by a lack of generality so the menthyl route has been nearly abandoned. Herein we provide a general solution to this long-standing problem and describe a general synthesis of menthyl H-phosphinate and disubstituted phosphinate esters. The method to prepare these versatile precursors relies on a simple and inexpensive process avoiding the use of phosphorus trichloride, Grignard reagents, and complicated cryogenic crystallizations. Established protocols can then be employed to synthesize P-stereogenic secondary and tertiary phosphine oxides and therefore P-stereogenic phosphine ligands.

Pyrophosphate analogues are of great importance especially for the design of biologically active molecules. The phospha-Claisen condensation allows for the rapid synthesis of (phosphonomethyl)phosphinate pyrophosphate analogues and building blocks that can be employed in numerous applications.

Manganese catalyzed reactions of H-phosphinates with various alkenes give the corresponding alkylated products.

The Mn(II)/Mn(IV) system was used to achieve the bisfunctionalization of alkenes with phosphorus and chlorine in moderate to good yields. A variety of phosphinylidene-containing (P(O)H) compounds were examined. When the phosphorus reagent is limiting, the reaction yield is generally in the 40–50% range, although the structure of the organophosphorus starting material greatly influences it. The reaction is simple and inexpensive and the β-chloro-phosphinoyl products are versatile intermediates. For example, elimination with DBU gave the corresponding α,β-unsaturated phosphorus compound stereoselectively.

A new family of chiral auxiliaries designed on a conformationally restricted version of (-)-8-phenylmenthol has been developed. Both enantiomers are available from an inexpensive synthesis conducted on multigram scale. A first application has showed comparable diastereoselectivity between the novel auxiliary and (-)-8-phenylmenthol.

A process for the conversion of hypophosphorous acid (H3PO2, HPA) and alcohols into various H-phosphonate diesters [(RO)2P(O)H] is described. The new reaction provides a missing bridge between HPA and important H-phosphonates, completely avoiding the use of PCl3. Nickel chloride or nickel on silica catalyze the oxidative phosphorylation of alkyl phosphinates with various alcohols or water. The reaction is atom economic and avoids the formation of waste products. The previous need for both chlorine and base is completely avoided.

A great leap forward toward the general synthesis of P-stereogenic compounds: Heating H3 PO2 with (-)-menthol and paraformaldehyde gives easily crystallized menthyl hydroxymethyl-H-phosphinate (1). From this product, virtually any P-stereogenic compound can be synthesized.

Organophosphorus compounds are important in everyday applications ranging from agriculture to medicine and are used in flame retardants and other materials. Although organophosphorus chemistry is known as a mature and specialized area, researchers would like to develop new methods for synthesizing organophosphorus compounds to improve the safety and sustainability of these chemical processes. The vast majority of compounds that contain a phosphorus-carbon bond are manufactured using phosphorus trichloride (PCl3) as an intermediate. However, these reactions require chlorine, and researchers would like to avoid the use of PCl3 and develop safer chemistry that also decreases energy consumption and minimizes waste. Researchers have already proposed and discussed two primary strategies based on elemental phosphorus (P4 or Pred) or on phosphine (PH3) as alternatives to PCl3. However, phosphinates, an important class of phosphorus compounds defined as any compound with a phosphorus atom attached to two oxygens, R(1)R(2)P(O)(OR) (R(1)/R(2) = hydrogen/carbon), offer another option. This Account discusses the previously neglected potential of these phosphinates as replacements of PCl3 for the preparation of organophosphorus compounds. Because of their strong reductive properties, industry currently uses the simplest members of this class of compounds, hypophosphites, for one major application: electroless plating. In comparison with other proposed PCl3 surrogates, hypophosphorous derivatives can offer improved stability, lower toxicity, higher solubility, and increased atom economy. When their reducing power is harnessed to form phosphorus-carbon or phosphorus-oxygen bonds, these compounds are also rich and versatile precursors to organophosphorus compounds. This Account examines the use of transition metal-catalyzed reactions such as cross-coupling and hydrophosphinylation for phosphorus-carbon bond formation. Because the most important industrial organophosphorus compounds include compounds triply or quadruply bound to oxygen, I also discuss controlled transfer hydrogenation for phosphorus-oxygen bond formation. I hope that this Account will further promote research in this novel and exciting yet much underdeveloped area of phosphinate activation.

The room-temperature hydrophosphinylation of unactivated monosubstituted alkenes using phosphinates (ROP(O)H2) and catalytic NiCl2 in the presence of dppe is described. The method is competitive with prior palladium-catalyzed reactions and uses a much cheaper catalyst and simple conditions. The scope of the reaction is quite broad in terms of unactivated terminal olefins, proceeds at room temperature, often avoids chromatographic purification, and allows one-pot conversion to various organophosphorus compounds.

Two generally applicable systems have been developed for the cross-coupling of P(O)H compounds with Csp2X and related partners. Palladium catalysis using a ligand/additive combination, typically either xantphos/ethylene glycol or 1,1′-bis(diphenylphosphino)ferrocene/1,2-dimethoxyethane, with diisopropylethylamine as the base, proved to be generally useful for the synthesis of numerous PC containing compounds. Routinely, 2 mol% of catalyst are employed (less than half the amount typically employed in most other literature reports). In most cases, excellent results are obtained with a variety of electrophiles (RX, where R=alkenyl, allyl, alkynyl, etc.). The full account of our studies is disclosed, including tandem hydrophosphinylation/coupling and coupling/coupling for doubly catalytic phosphorus-carbon bond formation. The methodology compares favorably with any existing literature report. The use of an additive appears to be a generally useful strategy to control the reactivity of phosphinylidene compounds.

The vast majority of organophosphorus compounds is currently synthesized from phosphorus trichloride (PCl3), even though the final consumer products do not contain reactive phosphorus–chlorine bonds. In order to bypass phosphorus trichloride, significant interest has been devoted to functionalizing elemental phosphorus (P4, the precursor to PCl3), red phosphorus (Pred), or phosphine (PH3). Yet, other industrial-scale precursors are hypophosphorous derivatives (H3PO2 and its alkali salts), but their use as phosphorus trichloride replacements has been completely overlooked. Here, the case is made for an alternative approach to the industrial synthesis of organophosphorus compounds based on hypophosphites.

The alkylation of alkyl phosphinates and some H-phosphonate diesters is promoted by the base DBU. Only more reactive alkyl halides react in preparatively useful yields. However, the method provides easy access to important H-phosphinate building blocks, without the need for a protecting group strategy or metal catalysts. The reaction is conveniently conducted at, or below, room temperature. The preparation of methyl-H-phosphinate esters is particularly interesting as it avoids the heretofore more common use of methyldichlorophosphine MePCl2.

(Hydroxymethyl)phosphorus compounds are well-known and valuable compounds in general; however the use of (hydroxymethyl)phosphinates R(1)P(O)(OR(2))CH(2)OH in particular has been much more limited. The potential of this functionality has not yet been fully realized because the mild unmasking of the hydroxymethyl group was not available. The mild oxidative conversion of R(1)P(O)(OR(2))CH(2)OH into R(1)P(O)(OR(2))H using the Corey-Kim oxidation is described. Other reactions preserving the methylene carbon are also reported.

The first metal-catalyzed hydrophosphinylation of unsaturated hydrocarbons with H-phosphinic acids is described. A strategy to activate the PH bond through control of the tautomeric equilibrium using ethylene glycol is described. The reactions also avoid chromatographic purification.

The palladium-catalyzed cross-coupling reaction between H-phosphinate esters and chloroarenes or chloroheteroarenes is described. This reaction is the first general metal-catalyzed phosphorus-carbon bond-forming reaction between a phosphorus nucleophile and chloroarenes.

The regioselectivity of the palladium-catalyzed hydrophosphinylation of terminal alkynes was investigated. Complementary conditions to achieve the predominant formation of either the linear or the branched alkenyl- H -phosphinate products were identified. With Pd/xantphos in acetonitrile, the linear isomer is generally obtained with good to excellent selectivity, and E -stereospecificity. On the other hand, by using Pd/dppf in the non-polar solvent toluene, good selectivity for the branched alkenyl- H -phosphinate is typically observed. The role of various reaction parameters is studied.

Various heterocycles containing phosphorus and nitrogen are easily synthesized from readily available H-phosphinate building blocks. Aminomethylation of these H-phosphinates is followed by in situ cyclization through substitution or cross-coupling to produce novel heterocycles in moderate to good yields.

The design, synthesis, and evaluation of a series of novel inhibitors of aspartate transcarbamoylase (ATCase) are reported. Several submicromolar phosphorus-containing inhibitors are described, but all-carboxylate compounds are inactive. Compounds were synthesized to probe the postulated cyclic transition-state of the enzyme-catalyzed reaction. In addition, the associated role of the protonation state at the phosphorus acid moiety was evaluated using phosphinic and carboxylic acids. Although none of the synthesized inhibitors is more potent than N-phosphonacetyl-L-aspartate (PALA), the compounds provide useful mechanistic information, as well as the basis for the design of future inhibitors and/or prodrugs.

H-Phosphinates obtained through various methodologies are protected directly by the reaction with triethyl orthoacetate. The resulting products can be manipulated easily, andvarious synthetic reactions are presented. For example, application to the synthesis of aspartate transcarbamoylase (ATCase) or kynureninase inhibitors are illustrated. Other reactions, such as Sharpless' asymmetric dihydroxylation, or Grubbs' olefin cross-metathesis are also demonstrated. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The facile synthesis of various P–C–P compounds is described, based on the reaction of phosphorus carbenoids with organoboranes, followed by reaction with phosphorus electrophiles. Using this approach, symmetrically and differentially substituted 1,1-bisphosphorus compounds can be obtained in good yields. A number of novel P–C–P motifs are described for the first time.

Phosphonothioic and boranophosphonic acids have been structurally characterized for the first time by single X-ray crystallography. These two functional groups, and the corresponding phosphonic acid, were all conveniently synthesized in high yields from trityl H-phosphinic acid (Ph3CPO2H2). The resulting trityl-substituted series: Ph3CP(O)(OH)2, Ph3CP(S)(OH)2, Ph3CP(O)(BH3 −)(OH)]LH+ (L = Lewis base) is fully characterized by spectroscopic methods, and the structural characteristics are compared. The results indicate that boranophosphonic acids should be investigated anytime a bioactive phosphonic acid has been identified. The solid state arrangements of the synthesized compounds are also discussed.

The reactions of phosphinylidene-containing compounds with unactivated unsaturated hydrocarbons are reviewed. The review is organized by phosphorus-containing functional group types. Free-radical and metal-catalyzed additions of R1R2P(O)H to alkenes, alkynes, and related compounds deliver functionalized organophosphorus compounds RP(O)R1R2, including H-phosphinates, phosphinates, tertiary phosphane oxides, and phosphonates. The review covers the literature up to February 2008.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Hypophosphorous compounds (MOP(O)H(2), M = H, R(3)NH) effectively participate in metal-catalyzed C-P bond-forming reactions with allenes, dienes, and activated allylic electrophiles under mild conditions. The catalytic system Pd(2)dba(3)/xantphos is crucial to avoid or minimize the competitive reductive transfer-hydrogenation pathway available to hypophosphorous acid derivatives. Further investigation into the allylation mechanism provided access to the analogy allylic acetate-allylic phosphinate, which then led to the development of a Pd-catalyzed rearrangement of preformed allylic phosphinates esters and, ultimately, to a catalytic dehydrative allylation of hypophosphorous acid with allylic alcohols. The reactions disclosed herein constitute efficient synthetic approaches, not only to prepare allylic H-phosphinic acids but also their esters via one-pot tandem processes. In addition, the potential of H-phosphinates as useful synthons for the preparation of other organophosphorus compounds is demonstrated.

Organoboranes react with phosphorus-containing carbenoids to produce a variety of functionalized organophosphorus compounds under mild conditions. In some cases, selective migration of one group attached to boron can be observed. Phosphonite-borane complexes are introduced as novel synthons for the synthesis of phosphinic esters.

A novel approach to H-phosphonates from hypophosphorous acid using a transfer hydrogenation process was developed. This method is atom-economical, environmentally friendly, catalytic, and efficient, leading easily to H-phosphonate monoesters or ammonium salt in moderate to good yields.

An efficient and general procedure was developed for the direct alkylation of H-phosphinate esters with LHMDS at low temperature. The simplicity of the reaction allows the use of various H-phosphinate esters and takes place with a wide range of electrophiles. The approach can be employed to access some GABA analogues or precursors to GABA analogues. The isolated yields are moderate to good. This is the first report of an alkylation with a secondary iodide or a primary chloride.

Phosphinylidene compounds R1R2P(O)H are important functionalities in organophosphorus chemistry and display prototropic tautomerism. Quantifying the tautomerization rate is paramount to understanding these compounds’ tautomerization behavior, which may impact their reactivities in various reactions. We report a combined theoretical and experimental study of the initial tautomerization rate of a range of phosphinylidene compounds. Initial tautomerization rates are found to decrease in the order H3PO2 > Ph2P(O)H > (PhO)2P(O)H > PhP(O) (OAlk)H > AlkP(O)(OAlk)H ≈ (AlkO)2P(O)H, where “Alk” denotes an alkyl substituent. The combination of computational investigations with experimental validation establishes a quantitative measure for the reactivity of various phosphorus compounds, as well as an accurate predictive tool.

Ethyl phosphinate adds to alkenes and alkynes under thermal radical conditions with AIBN as the initiator.

Simple alkyl phosphinates prepared by the silicate esterification method can be alkylated under Barbier-like conditions with butyl lithium at -78 °C followed by warming to room temperature. The method is limited to the more reactive electrophile such as allylic bromides and alkyl iodides. With these electrophiles good yields of H-phosphinic acid esters are generally obtained in a straightforward manner.

The direct formation of H-arylphosphinates and related compounds can be accomplished using palladium catalysis. This full paper examines the scope and some mechanistic aspects of this phosphorus–carbon bond forming reaction. The reactions of alkenyl and allylic halides are also described for the first time. This novel cross-coupling provides a convenient access to a variety of substituted H-phosphinates.

This account summarizes the research conducted in our laboratory over the past five years. New methodologies were devised for the formation of P–C bonds with a focus on the reactions of hypophosphorous acid derivatives. Three types of reactions have been developed: palladium-catalyzed cross-coupling, room-temperature radical addition, and palladium-catalyzed addition. Our results are summarized in each of these areas and include some of our most recent data. (1) Our palladium-catalyzed cross-coupling has been extended to the direct coupling of alkyl phosphinates with a variety of aryl, heteroaryl, and even alkenyl electrophiles. (2) The addition of sodium hypophosphite under radical conditions is extended from alkenes to alkynes. (3) The catalytic addition of hypophosphorous compounds using palladium catalysts (hydrophosphinylation) is also discussed.

[reaction: see text] A reusable polymer-supported hydrophosphinylation catalyst is described for the preparation of H-phosphinic acids. The polystyrene-based ligand is prepared in one step from commercially available compounds. The polymeric catalyst generally gives good yields for a variety of substrates and is water- and air-tolerant, although the scope of alkenes and alkynes which can be employed is somewhat narrower than with our original xantphos/Pd(2)dba(3) catalyst.

Aryl, heteroaryl, and benzylic electrophiles can be coupled to in situ-generated alkylphosphinates (ROP(O)H2) in moderate to good yields using palladium catalysis. For the first time, electrophiles other than simple aryl iodides can be employed in an experimentally straightforward, one-pot reaction. The direct formation of H-phosphinic esters avoids the separate esterification of H-phosphinic (phosphonous) acids and is particularly useful in the case of nitrogen-containing heteroaromatics. The reaction significantly expands the scope of related palladium-catalyzed phosphorus-carbon bond-forming reactions. To cite this article: Z. Huang et al., C. R. Chimie 7 (2004).

Alkenyl bromides and triflates undergo palladium-catalyzed cross-coupling with anilinium hypophosphite to afford monosubstituted phosphinates (salts of alkenylphosphonous acids). The reaction is an extension of our previously reported methodology for the synthesis of aryl- and benzyl-phosphonous acids. Our preliminary results show that the best reaction conditions are observed with Pd(OAc)2/dppp as a catalyst, in refluxing benzene or tetrahydrofuran. This novel PC bond forming reaction is applied to the synthesis of (1,2,3,6-tetrahydropyridin-4-yl)-methylphosphinic acid (TPMPA), a selective competitive antagonist for GABAC receptors. The divergent synthesis proceeds through protected (1,2,3,6-tetrahydropyridin-4-yl)-phosphinic acid, a previously unknown isoguvacine-like GABA analog. This synthetic intermediate is also an ideal precursor to other biologically interesting GABA analogs.

Only a few methods have been described for the preparation of hypophosphite esters (alkyl phosphinates, ROP(O)H 2 ). As a result, comparatively few applications have been reported, and these intermediates have not been widely exploited in organophosphorus chemistry despite their synthetic potential. Herein, we describe a very general, practical, and high-yielding synthesis of hypophosphite esters, based on the reaction of hypophosphorous acid and some of its salts with alkoxysilanes. This methodology solves a number of the problems associated with previously reported reactions. Our esterification takes place at moderate temperature in a variety of solvents, and under these conditions the esters are remarkably thermally stable. Furthermore, the reagents employed are inexpensive and do not have to be strictly anhydrous. The scope and limitations of the method are discussed, and representative synthetic applications for the preparation of monosubstituted phosphinate esters are described.

The intermolecular radical functionalization of arenes with aryl and alkyl H-phosphinate esters, as well as diphenylphosphine oxide and H-phosphonate diesters, is described. The novel catalytic Mn(II) /excess Mn(IV) system is a convenient and inexpensive solution to directly convert Csp2 H into CP bonds. The reaction can be employed to functionalize P-stereogenic H-phosphinates since it is stereospecific. With monosubstituted aromatics, the selectivity for para-substitution increases in the order (RO)2 P(O)H

[4886-44-6] CH5O3P (MW 96.02) InChI = 1S/CH5O3P/c2-1-5(3)4/h2,5H,1H2,(H,3,4) InChIKey = SIGZYWRTSGWBNO-UHFFFAOYSA-N Alternate Names: hydroxymethyl-H-phosphinic acid. Physical Data: not isolated. Solubility: soluble in water. Form Supplied in: generated in situ and used crude after concentration. Contains H3PO2 and/or (HOCH2)2P(O)OH as impurities. Handling, Storage, and Precautions: H-phosphinic acids can disproportionate thermally to form phosphines, so excessive heating must be avoided. Use in a fume hood.

A novel and practical approach to monosubstituted phosphinic acid (alkylphosphonous acid) derivatives from hypophosphite salts or esters is described. Phosphorus-centered radical formation is initiated with Et(3)B/O(2), and the reaction is conveniently conducted at room temperature in an open flask. In contrast to previously reported conditions for the radical reaction of hypophosphorous acid and sodium hypophosphite (peroxide initiators, acid catalysis, heat), the method proceeds under neutral conditions and therefore tolerates a wide range of functional groups. Previously inaccessible phosphinic acids can be prepared in a single step from cheap starting materials. Excellent selectivity is observed for monoaddition, and symmetrical dialkyl phosphinates do not form in significant amounts. Monosubstituted phosphinic acids are usually obtained in better than 90% purity by a simple extractive workup; however, isolated yields are diminished if the substituent is polar. Because radicals derived from hypophosphites are electrophilic, the reaction is limited to the use of electron-rich olefins. The reaction conditions can also be employed in the room temperature radical reduction of alkyl halides and provide an exceptionally mild and environmentally friendly alternative to the use of tributyltin hydride. The remarkable mild nature of the reaction conditions allows for the radical reaction of sensitive alkyl hypophosphites to occur, in which case, a catalytic amount of Et(3)B suffices to deliver alkyl phosphinate esters in reasonable yield.

This review provides an overview of recent efforts towards the synthesis of phosphinate heterocycles R1R2P(O)(OR). Our laboratory and others’ have been involved in this field and as a result new P–C, P–N, and P–O containing heterocyclic motifs are now available through a variety of methods. While developing rapidly, this area is still in its infancy so that biological testing of the compounds has not yet been conducted and applications are rare. The growing availability of synthetic methods will undoubtedly change this situation in the near future.