Synthesis of Phosphinic Acid Derivatives; Traditional Versus up-to-Date Synthetic Procedures

Copyright: © 2014 Keglevich G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Synthetic methods for the preparation of phosphinic derivatives (esters and amides) are summarized. The basic method is, when phosphinic chlorides are reacted with alcohols or amines. These reactions take place under mild conditions, but utilize expensive chlorides, need a solvent, and a base has to be added to remove the HCl formed. On conventional heating, the phosphinic acids resist undergoing derivatizations by nucleophiles. However, on microwave (MW) irradiation, the phosphinic acids could be esterified by alcohols. The direct esterification does not require an extra solvent, it is atomic efficient, but needs a relatively higher temperature. The similar amidations were reluctant. Phosphinic acids may also be esterified by alkylation that may be promoted by combined phase transfer catalysis and MW irradiation. It is also possible to convert the phosphinic acids by different reagents (e.g. by the T3P reactant) to a more reactive intermediate that is ready to react with alcohols or amines. Other methods, such as preparation by the Arbuzov reaction or by fragmentation-related phosphorylation are also discussed.


Introduction
Phosphinic derivatives (acids, chlorides, esters, amides etc.) are important building blocks (starting materials and intermediates) in synthetic organic chemistry [1]. They are produced on an industrial scale, and utilized in the synthesis of fine chemicals, plant protecting agents and medicines. Until now, there has been no comprehensive review on the synthesis of phosphinic derivatives. For this we undertook to compile this review including also our quite experiences. The discussion has been grouped around two major point of views: traditional syntheses and green chemical aspects.

Traditional Methods for the Synthesis of Phosphinate irect Esterification
It is known, that phosphinic acids cannot be esterified by alcohols (Scheme 1).

Scheme 2
Cherbuliez substantiated that the direct esterification of tetracoordinated P-acids with at least one P-H bond is only possible via the tautomeric tri coordinated form [4]. The direct esterification of orthophosphoric acid with ethanol yielded 2.5% of the monoethyl ester after 22 days, at the same time, the esterification of phenyl-H-phosphinic acid with an excess of ethanol gave 12% of the ethyl phenyl phosphinate after a reflux of 42h (Scheme 3). One patent reports the esterification of dialkylphosphinic acids in the presence of different catalysts under quite extreme conditions and prolonged reaction times (Scheme 4) [5].

Scheme 4
In another patent, authors claimed that two phosphinates were synthesized from the corresponding phosphinic acids by reaction with 2 equiv. of allyl or crotyl alcohol in the presence of p-toluenesulfonic acid in aromatics with water removal. However, there was no evidence for the formation of the esters [6].
It is remarkable, that no other example for the direct esterifications of phosphinic acids have been reported. However, diphenylphosphinothioates were prepared by the direct esterification of diphenylphosphinodithioic acid with certain alcohols and phenols in the absence of a catalyst [7].The reaction required long reaction times.

Scheme 7
Mixed anhydrides of Y 1 Y 2 P (O)O-C(O)OR type can be formed easily that undergo CO 2 elimination to provide the Y 1 Y 2 P(O)OR phosphinate [34].

Esterification of Phosphinic Chlorides with Alcohols
The usual synthesis of phosphinic esters involves the reaction of phosphinic chlorides with alcohols (Scheme 5) [1,[8][9][10], It is drawback that this method applies chlorides and an aromatic solvent, the acylation is not atomic efficient and environmentally problematic due to the formation of hydrochloric acid.

Scheme 5
In most cases a tertiary amine [11], an alcoholate [12] or a phenolate is used in a polar solvent [13]. Despite the disadvantages, this method is widely used due to its general applicability.
A few examples were described for the esterification of chlorophospholene oxides by alcohols in the presence of NEt 3 or NaOMe as the base in different solvents. The preparative details can be seen ( Table  1). The yields were variable (27-85%) [14][15][16][17][18].

Alkylating Esterification of Phosphinic Acids
Phosphinates may also be obtained by O-alkylation [7][8][9]. In the first step, the acid is transformed into the corresponding sodium or potassium salt that is then reacted with an alkyl halide. However, only a few examples were described (Scheme 6) [19,20].

Esterification of Phosphinic Acids by Orthocarbonyl Compounds
Alkyl hypophosphinates (H 2 P(O)OR) that are starting materials in the synthesis of alkyl-and aryl phosphinates, are prepared through the alkaline hydrolysis of P 4 in an industrial scale, [35] however, a few alternative methods were also described for their preparation. Fitch reported the reactions of hypophosphorous acid with compounds having an orthocarbonyl function, such as orthoesters (n=0), orthocarboxylates (e.g. orthoformates/orthoacetates) (n=1), ketals and acetals (n=2) [36] . Schwabacher studied the reaction of anhydrous hypophosphorus acid and trimethylorthoformate, that is a specific but not a clean method for the preparation of methyl phosphinate [37]. The reaction of ketals and acetals required higher temperatures and resulted in the formation of 1-hydroxyphosphinates [36]. A Japanese research group has carried out the synthesis of phosphinic esters with trialkyl orthocarboxylates, such as trialkyl orthoacetates in ionic liquid applying lower reaction temperatures and shorter reaction times [38].

Esterification of Phosphinic Acids by Orthosilicates
Montchamp has studied the esterification of H-phosphinic acids or their salts using orthosilicates or alkoxysilanes in detail [39,40]. The same group prepared stable hypophosphite esters by the reaction of hypophosphorus acid salts with aminoalkoxysilanes [40].

Scheme 9
Primary alkyl halides react faster than secondary, while tertiary alkyl halides usually fail to enter in the Arbuzov reaction. The reaction of aryl halides of decreased reactivity may be promoted by Ni salts (at higher temperatures) [44,45]. Vinyl halides may react in the presence of Cu (I) bromide [46].

P-C Bond formation from H-Phosphinates or Hypophosphinate
The Hirao reaction has been applied widely to form P-C bond in the coupling of aryl halides or other derivatives with >P(O)H reagents, mainly dialkyl phosphites in the presence of a complex catalyst [50]. In a modification, alkyl-H-phosphinic acids were coupled with aryl halides to give phosphinates (Scheme 11) [51].

Scheme 11
Zhao obtained the same type of P-C coupled products using CuI /proline catalysts [52], but Ni salts can also be applied as catalysts [53] .Mont champ and co-workers synthesized a variety of dialkylphosphinates by different organometallic reagents in the phosphorylation of alkyl and alkenyl derivatives [54].
Dialkylphosphinates were obtained via the Pd-catalyzed hydrophosphinylation of olefins [55]. Several applications were described for the combination of the above mentioned methods. Sterically hindered unsymmetrical diarylphosphinates were synthesized starting from hypophosphorous acid and applying an esterification step by orthoacetate that was followed by a palladium-catalyzed P-C bond formation step [56]. Another example is a one-pot process including an esterification step by aminoalkoxysilanes followed by a P-C coupling step giving rise to phenyl-H-phosphinates [57].

Formation of Cyclic Phosphinates from Phosphonium Salts
Cyclic phosphinates may be obtained by the alcoholysis of the

Scheme 12
The original procedure involving the alcoholysis of the cycloadduct (X = Br) was modified by the senior author of this chapter applying an excess of the alcohol as the solvent, and solid sodium carbonate, as the base resulting in the alkoxy-3-phospholene 1-oxides in better (57-68%) yields [60,61].

Formation of Cyclic Phosphinates by Ring Closure
Bis-Grignard reagents may be used in the synthesis of phospholane oxide derivatives. An example is the ring closure of the bis (Grignard reagent) obtained from 2,5-dibromopentane and magnesium by EtOP(O)Cl 2 that resulted in the formation of 1-ethoxy-2,5dimethylphospholane 1-oxide [65].

Alcoholysis of Phosphinic Derivatives
Reaction of phosphinates with alcohols is also a known procedure that is accomplished by heating of the given esters with higher boiling point alcohols for a longer period of time [68]. Although several examples can be found for the "transesterification" of phosphinates by alcohols, it can be said that these reactions, in most cases, lead only to incomplete conversions [37,39,40,69].

Phosphinates by the Atherton-Todd Reaction
The reaction of secondary phosphine oxides with alcohols under the conditions of the Atherton-Todd reaction may give phosphinates (Scheme 17) [93] .

Phosphinates by Rearrangement Reactions
Interestingly, the treatment of diaryl ethyl phosphates with lithium diisopropylamide led to the corresponding ethyl diarylphosphinates by a double rearrangement after hydrolysis [94]. On the other hand 3-aryl-3-phospha-1,5-hexadienes may furnish phosphinates via a phospha-Cope rearrangement. The reaction of the intermediate so formed with an alcohol gives phosphinates [95].

Reaction of Phosphinic Chlorides with Amines
The most general method for the preparation of phosphinic amides is the reaction of phosphinic chlorides with primary or secondary amines. In these cases, the hydrochloric acid formed can be removed by a second equivalent of the amine (Scheme 18) [1,[8][9][10]13,96].

Scheme 19
In rare cases, the corresponding bromide was used instead of the phosphinic chloride [99]. The reaction of primary amines with 1-chloro-3-phospholene 1-oxides prepared from the corresponding hydroxy-phospholene 1-oxides was studied by the authors this chapter [100]. It was found, that depending on the molar ratio of the reactants and on the order of mixing, the reaction afforded either 1-aminophospholene 1-oxides (A), or their N-phosphinoyl derivatives (B) (Scheme 20). Thus, the product composition could be fine-tuned.

Miscellaneous Methods
Analogously to phosphinates, phosphinic amides may also be synthesized by the Atherton-Todd reaction using secondary phosphine oxides and amines as the nucleophiles [93,103].
The reaction of 1-hydroxy-3-methyl-3-phospholene 1-oxide with tris(N,N-dialkylamino)phosphines afforded the corresponding aminophospholene oxide via three steps. The key intermediates were the corresponding salt and an anhydride that underwent a transamination reaction to afford amino-phospholene oxides in good yields (Scheme 23) [98].

Green Methods for the Synthesis of Phosphinates and Phosphinic Amides Green Methods for Phosphinates
It was shown in subchapter 2.2. that the traditional synthesis of phosphinates by the reaction of phosphinic chlorides and alcohols is not green due to the need of solvent and base, and the reaction is not atomic efficient as a consequence of the formation of HCl. It would be a "greener" procedure to start from the corresponding phosphinic acid. The formation of H 2 O as the by-product would mean a better atomic efficiency. The microwave (MW) and the phase catalytic techniques offer good possibilities to perform environmentallyfriendly transformations.

Direct Esterification of 1-Hydroxy-3-Phospholene 1-Oxides
With Butyl Alcohol: It was shown in subchapter 2.1. that the phosphinic acids usually do not undergo direct esterification. This is well exemplified by the fact that 1-hydroxy-3-methyl-and -3,4-dimethyl-3phospholene oxides cannot be esterified with butyl alcohol on heating. However, we found, that on MW irradiation at 22°C/8 bar, applying the alcohol in a 15-fold excess, the corresponding phosphinates were obtained in 44

Scheme 25
Both the MW and the comparative thermal experiments were accomplished in sealed reaction vessels. Regarding the MW-assisted reactions, the distribution of the temperature may be regarded macroscopically isotherm in the bulk of the mixture. However, in nanosegments there is a statistically occurring local overheating effect that is very efficient in promoting faster and more quantitative reactions.
With longer carbon atom chain alcohols: Later on we found that it is more advantageous to use longer carbon atom chain, and hence less volatile alcohols as the reagents. In these cases, even a higher reaction temperature (up to 235°C) may be applied and the overpressure developed is only 1-1.5 bar. Carrying out the esterifications of and the transformation is slightly endothermic, let say thermoneutral (Figure 1/b). It is a noteworthy finding that both direct esterifications under discussion involve a 4-membered ring transition state (TS) formed from the protonated acid in a one elementary step process (Figure 2/a,b). Analogous TSs was also assumed for other type of reactions, such as for trans esterifications and hydrolytic processes [113]. It is important to stress that these results were obtained for gas phase reactions. It is obvious that the direct esterification of phosphinic acids is prevented on conventional heating by the relatively high values for the enthalpy of activation. However, the beneficial effect of the statistically occurring local overheatings may promote to overcome the energy barrier.

Possible Mechanisms for the Formation of Esters by the Reaction of Phosphinic Esters with Alcohols:
Basically, the reaction of phosphinic acids and alcohols may take place by the phosphorylation of the alcohol, or by the alkylation of the phosphinic acid (Scheme 30). The classical "acylation" route is represented by protocol "A", while the novel sequence including the above-mentioned 4-center TS is shown by protocol "B". The esterification by the alkylation of the phosphinic 1-hydroxy-3-methyl-and -3,4-dimethyl-3-phospholene oxides with n-pentyl alcohol, i-pentyl alcohol, n-octyl alcohol, i-octyl alcohol and dodecyl alcohol, the cyclic phosphinates were obtained in yields of 57-95%, after almost quantitative conversions (Scheme 26) [109][110][111].

Direct Esterification of 1-
In respect of the cyclic phosphinic acids, the following order of reactivity was observed: n respect of the reagents used, the MW-assisted direct esterification of phosphinic acids may be regarded green. However, the need for a reaction temperature of ca. 200°C may mean a disadvantage. If a professional MW reactor is available, the assurance of the relatively higher reaction temperature is not a problem.

Energetics of the Direct Esterification:
The energetics of the esterification of phosphinic acids was evaluated by B3LYP/6-31++G (d,p) calculations in comparison with that of acetic acid. In these cases a single alcohol molecule was assumed [112]. It was found that the formation of methyl acetate goes with an enthalpy of activation of 75 kJ mol -1 and the reaction is slightly exothermic (Figure 1/a). At the same time, the esterification of 1-hydroxy-3-methyl-3-phospholene oxide with butyl alcohol has a higher activation barrier of 102 kJ mol -1

Mechanism of the Esterification of 1-Hydroxy-3-Methyl-3-Phospholene oxide with Butanol using the Explicit -Implicit Solvent
Model: A more reliable explicit-implicit solvent model was constructed by the consideration of a few solvent molecules and an additional phosphinic acid as a proton donor in the starting state as illustrated in Scheme 27 [112]. The two Bu OH (solvent) molecules form an important hydrogen bond net in the associate. The esterification starts with the nucleophilic attack of the oxygen of BuOH on the P=O group of the reactant, resulting in a rather unstable (131.1 kJ mol -1 ) first intermediate state, via high energy TS1 (134.6 kJ mol -1 ). Then, the following low energy multistep transformation involves proton transfers through the two butanol molecules. In the final step, the phosphinic acid catalyst helps the departure of the OH group form the P atom of the second intermediate by protonation via a high energy TS2 (133.5 kJ mol -1 ). The activation enthalpies of the last steps are somewhat lower, than those for the first TS1, therefore the reaction rate is controlled by the first nucleophilic attack of BuOH. The overall process is entropically driven by the elimination of water, but the nonbeneficial enthalpy could not be compensated by that. In the light of the activation enthalpies computed, the nominal temperature of 180-235°C and even the local overheatings caused by the MW irradiation could be essential to overcome the high activation Gibbs free energy. It can be concluded that MW may promote thermoneutral reactions with relatively high enthalpies of activation.

Scheme 31
Esterification of 1-Hydroxy-3-Methyl-3-Phospholene-1-Oxide with a Thioalcohol: It was not so surprising that the MW-assisted direct esterification of 1-hydroxy-3-methyl-3-phospholene 1-oxide with thiobutanol resulted in the formation of the thiobutoxy-3phospholene oxide (Scheme 32) [114].The conversion was, however, only 51%, consequently, the isolated yield of the monothiophosphinate was only 38%. The experimental fact, that no 1-butoxy-3-phospholene oxide was formed confirmed the "acylation" mechanism. The question emerged what the reason may be that this reaction was so reluctant, even under MW irradiation. The energetics of the reaction under discussion was evaluated by quantum chemical calculations. We learned that as compared to the esterification with butanol, the enthalpy of activation was significantly higher (145 kJ mol -1 ) and what is more, the reaction turned endothermic (Figure 3/a and b). This explains why the esterification with thiobutanol remained incomplete. Endothermicity is against the beneficial effect of the local overheatings. The 4-membered TS established for this reaction is shown in (Figure 4)

Scheme 32
According to a more sophisticated computational study carried out with the explicit -implicit solvent model an even higher TS (230.5 kJ mol -1 ), was found and the endothermicity was (∆H = 47.9 kJ mol -1 ) by this method. This reaction route starts with the protonated hydroxyphospholene oxide getting the proton from another molecule of the phosphinic acid. It is noteworthy that although the species protonated on the P=O group is ca. 104.4 kJ mol -1 more stable than that protonated on the OH unit, it is still the latter form that reacts, although it is present only in a small quantity. This species is attacked by a thiobutanol molecule to form protonated thioester via a relatively high activation barrier (230.5 kJ mol -1 ) belonging to the corresponding TS. Deprotonation of the final intermediate affords the thiophosphinate (Scheme 33). The incompleteness of the reaction is explained rather by its high endothermicity, than its high overall activation barrier. The sterically hindered diphenylphosphinic acid was also esterified, but these reactions required somewhat more forcing conditions and the yields were lower (Scheme 35

Scheme 36
The phosphonic acid-ester derivatives could also be esterified by alcohols under MW conditions to furnish dialkyl phenylphosphonates in variable yields 35-62%, (Scheme 37). This is the first case for the MW-assisted direct esterification of phosphonic acid derivatives.

Alkylation Esterification of 1-Hydroxy-3-Phospholene 1-Oxides:
The senior author of this chapter, together with others studied the alkylating esterification of cyclic phosphinic acids under phase transfer catalytic (PTC) and solvent-free microwave (MW) conditions using alkyl halides in the presence of potassium carbonate [109,116].
Carrying out the alkylation of 1-hydroxy-3-methyl-and -3,4-dimethyl-3-phospholene oxides with alkyl halides of normal reactivity, such as ethyl iodide, n-propyl bromide and butyl bromide, the simultaneous use of the phase transfer catalyst (triethylbenzylammonium chloride [TEBAC]) and MW was beneficial (Scheme 38). The alkylations carried out on conventional heating led to somewhat lower yields as compared to the MW variations. The alkylation with the sterically hindered i-propyl bromide was not so efficient. It was found, that in case of benzyl bromide that is of increased reactivity the phase transfer catalyst could be omitted, thus a solventand catalyst-free method was developed.

Alkylating Esterification of Hydroxy-phospholane Oxide:
Similar trends were experienced in the phase transfer catalyzed (PTC) and MW-assisted alkylating esterification of 1-hydroxy-3-methyl-and -3,4-dimethylphospholane oxides (Scheme 39). The esterifications with n-butyl bromide could be enhanced by the addition of TEBAC as the catalyst at 100°C. However, at 120°C there was no need for the catalyst. Similarly to the direct esterifications, the monomethyl cyclic phosphinates were obtained as a mixture of two isomers, while the dimethyl derivatives as a mixture of three isomers.
It was shown recently that the alkylating esterification of phenyl-Hphosphinic acid with alkyl halides takes place using triethylamine in a homogeneous medium (Scheme 37) [117]. The propylphosphonic anhydride (T3P ® ) reagent is also a powerful coupling (dehydrating/condensing) agent applied in a wide range of reactions [118]. The senior author of this article together with co-workers reported the fast and efficient esterification of cyclic phosphinic acids with a series of alcohols at 25°C, in the presence of 1.1 equivalent of the T3P ® reagent (Scheme 42). [119].

Me
A 75%

Scheme 45
The role of the T3P ® reagent is to form a reactive anhydride intermediate from the cyclic phosphinic acid, which may then undergo reaction with the alcohol already at room temperature. Phosphinates by P-Ligand-free P-C Coupling: An environmentally friendly approach for the synthesis of arylphosphinates by the Hirao reaction of phenyl-H-phosphinate with bromobenzene involves the use of P-ligand-free Pd(OAc) 2 catalyst under solvent-free MW conditions as this was observed by the senior author of this chapter together with

Scheme 48
Theoretical calculations on the amidation of acetic acid and 1-hydroxy-3-methyl-3-phospholene oxide suggested that the amidation of acetic acid is slightly exothermic, while that of the cyclic phosphinic acid is significantly endothermic (-8.2 vs. 32.6 kJ mol -1 ). The enthalpies of activation are not too high (-52.1 vs. 79.4 kJ mol -1 ) [121]. The energetics of the direct amidations discussed in comparison are shown in (Figure 5), while the TS for the amidation of 1-hydroxy-3-methyl-3-phospholene oxide with hexylamine can be seen in (Figure 6). Endothermicity works against the beneficial effect of MW irradiation. Theoretical calculations at the B3LYP/6-31G(d,p) level of theory utilizing the solvent model [112] showed that the amidation of 1-hydroxy-3-methyl-3-phospholene oxide by hexylamine, analogously to the thioesterification, also exhibits a rather endothermic enthalpy profile (35.2 kJ mol -1 ), which means an unfavourable course for the reaction. According to a detailed study [112] the mechanism starts with a proton exchange pre-equilibrium between hexylamine and cyclic phosphinic acid. The resulting phosphinic acid anion is, however, inactive toward the amine nucleophile, consequently, the series of elemental steps starts from the neutral form of the phosphinic acid that is attacked by the hexylamine. In the quantum mechanical model shown in (Figure 7), a protonated hexylamine molecule (HexNH 3 + ) acts as an acid catalyst, while an additional HexNH 2 molecule behaves as base catalyst in the course of the reaction. After a few steps, the reaction sequence ends up by the elimination of a molecule of water to afford the amide as the final product. The enthalpy of activation corrected by the energy gain of the protolytic equilibrium is moderate (114.1 kJ mol -1 ) as compared to that of the esterification and thioesterification.  The results show undoubtedly that the amidation under discussion is controlled by the endothermic pattern and the kinetic energy gap. It can be concluded that the reluctancy of the amidation of the phosphinic acids, in the case under discussion 1-hydroxy-3-phospholene oxide, is explained by the endothermicity. MW may promote only exothermic or thermoneutral transformations.

Conclusions
The possible synthetic methods for phosphinic derivatives have been summarized. On the one hand, the traditional methods starting form phosphinic chlorides or phosphinic acids via activation (e.g. by the T3P reagent) to give phosphinates and phosphinic amides mean a good choice for the preparation. These common methods are completed well by more special reactions, such as the Arbuzov reaction, Hirao reaction, alcoholysis, fragmentation-related phosphorylation and other approaches, like intramolecular cyclization and the alcoholysis of phosphonium salts. On the other hand, there are "greener" variations