The Hydrolysis of Phosphinates and Phosphonates: a Review

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Review The Hydrolysis of Phosphinates and Phosphonates: A Review

Nikoletta Harsági and György Keglevich *

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] * Correspondence: [email protected]; Tel.: +36-1-463-1111 (ext. 5883)

Abstract: Phosphinic and phosphonic acids are useful intermediates and biologically active compounds which may be prepared from their esters, phosphinates and phosphonates, respectively, by hydrolysis or dealkylation. The hydrolysis may take place both under acidic and basic conditions, but the C-O bond may also be cleaved by trimethylsilyl halides. The hydrolysis of P-esters is a challenging task because, in most cases, the optimized reaction conditions have not yet been explored. Despite the importance of the hydrolysis of P-esters, this ﬁeld has not yet been fully surveyed. In order to ﬁll this gap, examples of acidic and alkaline hydrolysis, as well as the dealkylation of phosphinates and phosphonates, are summarized in this review.

Keywords: hydrolysis; dealkylation; phosphinates; phosphonates; P-acids

1. Introduction Phosphinic and phosphonic acids are of great importance due to their biological activity (Figure1)[ 1]. Most of them are known as antibacterial agents [2,3]. Multidrug- resistant (MDR) and extensively drug-resistant (XDR) pathogens may cause major problems Citation: Harsági, N.; Keglevich, G. in the treatment of bacterial infections. However, Fosfomycin has remained active against The Hydrolysis of Phosphinates and both Gram-positive and Gram-negative MDR and XDR bacteria [2]. Acyclic nucleoside Phosphonates: A Review. Molecules phosphonic derivatives like Cidofovir, Adefovir and Tenofovir play an important role 2021, 26, 2840. https://doi.org/ in the treatment of DNA virus and retrovirus infections [4]. Some P-esters have also 10.3390/molecules26102840 been shown to be effective against Hepatitis C and Influenza A virus [5], and some are known as glutamate and GABA-based CNS therapeutics [5–7]. Glutamate is a main Academic Editor: Georg Manolikakes excitatory neurotransmitter, so agonists of the metabotropic glutamate receptor can be new therapeutic targets for brain disorders (schizophrenia, Parkinson’s disease, pain). GABA is a Received: 19 April 2021 main inhibitory neurotransmitter which is responsible for neurological disorders (epilepsy, Accepted: 6 May 2021 anxiety disorders). Dronates are known to increase the mineral density in bones [8,9]. Published: 11 May 2021 Moreover, P-esters include antimalarial agents [5,10,11], anticancer agents [5,12–14] and angiotensin-converting enzyme (ACE) inhibitors [15]. In addition, the use of P-acids as Publisher’s Note: MDPI stays neutral herbicides (glyphosate, glyfosinate) [5,16] is not negligible either. Phosphinic acids are with regard to jurisdictional claims in of interest due to their ability to inhibit metalloproteases [17]. Methylphosphonic acid is published maps and institutional affil- known as a flame retardant [18]. During the preparation of these compounds, an ester- iations. protecting group is introduced into the molecule, and the hydrolysis of the ester group is necessary in the final steps. For a long time, water was used as the solvent only in hydrolyses. Despite its favorable properties (cheap, available, safe and “green”), water could not spread as a general solvent. Copyright: © 2021 by the authors. This is due to the low solubility of organic substrates. The application of co-solvents, such Licensee MDPI, Basel, Switzerland. as alcohols, DMF, acetone and acetonitrile is a good possibility. However, the regeneration This article is an open access article of water or water–solvent mixtures is not easy. distributed under the terms and Despite their great importance, the hydrolysis of P-esters has not been adequately conditions of the Creative Commons studied. Often, unoptimized routine hydrolyses were described or the kinetics of these Attribution (CC BY) license (https:// processes were studied. In most cases, the esters were reacted under harsh conditions with creativecommons.org/licenses/by/ 4.0/). a large excess of concentrated acid, and often the applied reaction time was longer than

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necessary. Hydrolyses can be catalyzed by acids and bases as well (Scheme1)[ 19]. Acidic hydrolyses can be catalyzed both by mineral and Lewis acids [20]. Mineral acids are mostly hydrogen halides [21], e.g., hydrochloric acid [22–27], but hydrobromic acid [28–32] proved to be more efﬁcient. Despite this, the application of hydrochloric acid was widespread. The hydrolyses were generally performed at around 100 ◦C with longer reaction times [20]. There are also examples when triﬂuoroacetic acid (TFA) [17,33,34] or HClO4 [35,36] was used to catalyze the hydrolyses. Sodium hydroxide is the most commonly used reagent in alkaline hydrolysis [37–41], but there are also examples of the application of KOH [42], LiOH [40,43] and NaHCO3 [44]. The alkaline hydrolysis is irreversible and less corrosive, but alkali-sensitive molecules can be damaged. A further disadvantage is that the base-

Molecules 2021, 26, x FOR PEER REVIEWcatalyzed hydrolyses take place in two steps: ﬁrst, the sodium-salt of the acid is formed,2 of 35 then the corresponding acid is liberated. In the case of acid catalysis, the P-acids are obtained directly.

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FigureFigure 1.1. AA fewfew biologicallybiologically activeactive phosphinicphosphinic andand phosphonicphosphonic acids.acids.

For a long time, water was used as the solvent only in hydrolyses. Despite its favorable properties (cheap, available, safe and “green”), water could not spread as a general solvent. This is due to the low solubility of organic substrates. The application of co-solvents, such as alcohols, DMF, acetone and acetonitrile is a good possibility. However, the regeneration of water or water–solvent mixtures is not easy. Despite their great importance, the hydrolysis of P-esters has not been adequately studied. Often, unoptimized routine hydrolyses were described or the kinetics of these processes were studied. In most cases, the esters were reacted under harsh conditions with a large excess of concentrated acid, and often the applied reaction time was longer than necessary. Hydrolyses can be catalyzed by acids and bases as well (Scheme 1) [19]. Acidic hydrolyses can be catalyzed both by mineral and Lewis acids [20]. Mineral acids are mostly hydrogen halides [21], e.g., hydrochloric acid [22–27], but hydrobromic acid [28– 32] proved to be more efficient. Despite this, the application of hydrochloric acid was Scheme 1. The most commonly used strategies to prepare P-acids. widespread. The hydrolyses were generally performed at around 100 °C with longer re- actionDuring times hydrolysis, [20]. There aare nucleoph also examplesilic attack when occurs trifluoroacetic on the phosphorus acid (TFA) atom [17,33,34] of the P=O or unitHClO [45].4 [35,36] In most was of usedthe cases, to catalyze the P-O the bond hydrolyses. is cleaved Sodium during thehydroxide acid- and is base-catalyzedthe most com- hydrolyses.monly used The reagent rate inof alkalinehydrolysis hydrolysis may be in[37–41],fluenced but by there the arepH also[35,36] examples and by ofthe the ionic ap- strengthplication of of the KOH medium, [42], LiOH but the[40,43] type and of ionNaHCO added3 [44]. to the The system alkaline is alsohydrolysis decisive. is irreversible andThere less are corrosive, a few cases but when alkali-sensitive the desired molecules P-acid is notcan prepared be damaged. by hydrolysis, A further butdisad- by thevantage cleavage is that of thethe C-Obase-catalyzed bond, which hydrolyses is possible take by pyrolysisplace in two [46] steps: or in first,reaction the withsodium- tri- methylsilylsalt of the acid halides is formed, (Scheme then 1) [47–52],the correspond boron tribromideing acid is [53],liberated. or various In the amines case of [54–56].acid ca- Dealkylationstalysis, the P-acids with aretrimethylsilyl obtained directly. halides takes place under mild conditions, such that they can also be used for the hydrolysis of esters in which instances strong acidic or alkaline treatments cannot be applied, such as in the cases of nitriles, vinyl ethers and acetals [57–59]. In addition, various enzyme-catalyzed [60–72] hydrolyses have also been elaborated, and there are examples for the application of special catalysts and metal ions as well [73–77]. It is important to mention that P-acids can also be prepared indirectly (Scheme 2). In this case, the ester (1) is converted to the corresponding acid chloride (2), which is a more reactive derivative, and can react with water at room temperature [78,79]. This method cannot be considered as a good solution from the point of view of its number of steps and

atomic efficiency.

Scheme 2. Indirect preparation of a ring P-acid.

In this survey, we discuss the acidic hydrolysis of phosphinates and phosphonates. This is followed by the presentation of the alkaline and basic hydrolysis of phosphinates and that of phosphonates. The reactivity of the different substrates, the effect of the substituents, and their green chemical aspects are the focus. Last but not least, the conversion of P-esters to acids by dealkylation is summarized.

2. Acidic Hydrolysis of Phosphinates and Phosphonates 2.1. Acidic Hydrolysis of Phosphinates In a paper published in 1973, Cook et al. compared the acid-catalyzed hydrolysis of methyl dialkylphosphinates (4) with base-catalyzed examples (Scheme 3) [80]. It was con-

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Molecules 2021, 26, 2840 Scheme 1. The most commonly used strategies to prepare P-acids. 3 of 33

During hydrolysis, a nucleophilic attack occurs on the phosphorus atom of the P=O unit [45]. In most of the cases, the P-O bond is cleaved during the acid- and base-catalyzed During hydrolysis, a nucleophilic attack occurs on the phosphorus atom of the P=O hydrolyses. The rate of hydrolysis may be influenced by the pH [35,36] and by the ionic unit [45]. In most of the cases, the P-O bond is cleaved during the acid- and base-catalyzed strength of the medium, but the type of ion added to the system is also decisive. hydrolyses. The rate of hydrolysis may be inﬂuenced by the pH [35,36] and by the ionic strengthThere of are the a medium, few cases but when the typethe desired of ion added P-acid to is the not system prepared is also by hydrolysis, decisive. but by the cleavageThere are of athe few C-O cases bond, when which the is desired possibleP-acid by pyrolysis is not prepared [46] or in by reaction hydrolysis, with buttri- bymethylsilyl the cleavage halides of the(Scheme C-O bond, 1) [47–52], which boron is possible tribromide by pyrolysis [53], or various [46] or inamines reaction [54–56]. with trimethylsilylDealkylations halideswith trimethylsilyl (Scheme1)[ 47 halides–52], boron takes tribromide place under [53 ],mild or various conditions, amines such [54 –that56]. Dealkylationsthey can also be with used trimethylsilyl for the hydrolysis halides of takes esters place in which under instances mild conditions, strong acidic such that or alka- they canline alsotreatments be used cannot for the be hydrolysis applied, such of esters as in inthe which cases instancesof nitriles, strong vinyl ethers acidic and or alkaline acetals treatments[57–59]. In cannotaddition, be applied,various enzyme-catalyzed such as in the cases [60–72] of nitriles, hydrolyses vinyl ethers have and also acetals been [ 57elabo-–59]. Inrated, addition, and there various are examples enzyme-catalyzed for the application [60–72] hydrolyses of special havecatalysts also and been metal elaborated, ions as well and there[73–77]. are examples for the application of special catalysts and metal ions as well [73–77]. It is important to mention that P-acids can also bebe preparedprepared indirectlyindirectly (Scheme(Scheme2 2).). In In this case, the ester (1) is converted to the corresponding acid chloride ((2),), whichwhich isis aa moremore reactive derivative, and can react withwith waterwater atat roomroom temperaturetemperature [[78,79].78,79]. ThisThis methodmethod cannot be considered as a good solution from thethe pointpoint ofof viewview ofof itsits number ofof stepssteps andand atomic efﬁciency.efficiency.

Scheme 2. Indirect preparation of a ring P-acid.-acid.

In this survey, wewe discussdiscuss thethe acidicacidic hydrolysishydrolysis of phosphinates and phosphonates. This isis followedfollowed by by the the presentation presentation of of the the alkaline alkaline and and basic basic hydrolysis hydrolysis of phosphinates of phosphinates and thatand ofthat phosphonates. of phosphonates. The reactivity The reactivity of the of different the different substrates, substrates, the effect the of effect the substituents, of the sub- P andstituents, their greenand their chemical green aspects chemical are aspects the focus. are Lastthe focus. but not Last least, but the not conversion least, the conversion of -esters to acids by dealkylation is summarized. of P-esters to acids by dealkylation is summarized. 2. Acidic Hydrolysis of Phosphinates and Phosphonates Molecules 2021, 26, x FOR PEER REVIEW2. Acidic Hydrolysis of Phosphinates and Phosphonates 4 of 35 2.1. Acidic Hydrolysis of Phosphinates 2.1. Acidic Hydrolysis of Phosphinates In a paper published in 1973, Cook et al. compared the acid-catalyzed hydrolysis of methylIn a paper dialkylphosphinates published in 1973, (4) Cook with base-catalyzedet al. compared examples the acid-catalyzed (Scheme3 )[hydrolysis80]. It was of concludedcludedmethyl dialkylphosphinatesthat thatpolar polar and andsteric steric (effects4) with effects hardly base-catalyzed hardly influence inﬂuence examples the acid-catalyzed the (Scheme acid-catalyzed 3) hydrolysis [80]. hydrolysisIt was com- con- comparedpared to the to base-catalyzed the base-catalyzed version. version. In a Insubsequent a subsequent publication, publication, they theydemonstrated demonstrated that thatthe hydrolysis the hydrolysis of the of methyl the methyl esters esters proceeds proceeds by the by rarely the rarely occurring occurring AAl2 AmechanismAl2 mechanism (wa- (waterter is involved is involved and and C-O C-O bond bond cleavage cleavage occurs) occurs) [81]. [81]. The The major major routes routes involve thethe AAAcAc2 mechanism (water is involved and P-OP-O bondbond cleavagecleavage occurs)occurs) andand thethe AAAlAl11 mechanismmechanism (water is not involved in the rate-determining step, and a C-O bond cleavage occurs) [82]. [82]. The mechanistic study was extended toto thethe hydrolysishydrolysis ofof additionaladditional estersesters [[82,83].82,83].

Scheme 3. Acid-catalyzed hydrolysis of methyl dialkylphosphinates (44).).

Bunnett et et al. al. studied studied the the hydrolysis hydrolysis of ofdifferent different methyl methyl methyl-arylphosphinates methyl-arylphosphinates (6) ◦ (at6) various at various HClO HClO4 concentrations4 concentrations (1–9 M) (1–9 and M) temperatures and temperatures (67.2, 95.1, (67.2, 107.6 95.1, °C) 107.6 (SchemeC) 4) [35]. The hydrolysis was found to be optimal at a 6–7 M acid concentration, above which the reaction became slightly slower.

Scheme 4. Hydrolysis of different methyl methyl-arylphosphinates (6) with HClO4.

The hydrolysis of p-nitrophenyl diphenylphosphinate (8) under acid catalysis was also studied (Scheme 5) [36]. The rate constant was determined at different acid concentrations in a dioxane–water mixture to ensure homogeneity. There is a maximum rate at 1.5 M HClO4. In more concentrated solutions, the acidic inhibition of the hydrolysis was observed.

Scheme 5. Hydrolysis of p-nitrophenyl diphenylphosphinate (8) under acid catalysis.

There were cases when alkaline hydrolysis proved to be slow at room temperature, but at higher temperatures it was too harsh for sensitive substrates. In these cases, acidic hydrolysis is more favorable. A good example is the acidic hydrolysis of a β-carboxamido- substituted phosphinic acid ester (10), as this is a rapid and gentle way to provide the corresponding phosphinic acid (11) quantitatively (Scheme 6) [17]. In this particular case, trifluoroacetic acid was the catalyst in an aqueous medium.

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cluded that polar and steric effects hardly influence the acid-catalyzed hydrolysis com- cluded that polar and steric effects hardly influence the acid-catalyzed hydrolysis compared to the base-catalyzed version. In a subsequent publication, they demonstrated that pared to the base-catalyzed version. In a subsequent publication, they demonstrated that the hydrolysis of the methyl esters proceeds by the rarely occurring AAl2 mechanism (wa- the hydrolysis of the methyl esters proceeds by the rarely occurring AAl2 mechanism (water is involved and C-O bond cleavage occurs) [81]. The major routes involve the AAc2 ter is involved and C-O bond cleavage occurs) [81]. The major routes involve the AAc2 mechanism (water is involved and P-O bond cleavage occurs) and the AAl1 mechanism mechanism (water is involved and P-O bond cleavage occurs) and the AAl1 mechanism (water is not involved in the rate-determining step, and a C-O bond cleavage occurs) [82]. (water is not involved in the rate-determining step, and a C-O bond cleavage occurs) [82]. The mechanistic study was extended to the hydrolysis of additional esters [82,83]. The mechanistic study was extended to the hydrolysis of additional esters [82,83].

Scheme 3. Acid-catalyzed hydrolysis of methyl dialkylphosphinates (4). Scheme 3. Acid-catalyzed hydrolysis of methyl dialkylphosphinates (4). Molecules 2021, 26, 2840 4 of 33 Bunnett et al. studied the hydrolysis of different methyl methyl-arylphosphinates (6) Bunnett et al. studied the hydrolysis of different methyl methyl-arylphosphinates (6) at various HClO4 concentrations (1–9 M) and temperatures (67.2, 95.1, 107.6 °C) (Scheme at various HClO4 concentrations (1–9 M) and temperatures (67.2, 95.1, 107.6 °C) (Scheme 4) [35]. The hydrolysis was found to be optimal at a 6–7 M acid concentration, above which (Scheme4) [35]. The4) hydrolysis[35]. The hydrolysis was found was to be found optimal to at be a optimal 6–7 M acid at a concentration, 6–7 M acid concentration, above which the reaction became slightly slower. theabove reaction which became the reaction slightly became slower. slightly slower.

Scheme 4. Hydrolysis of different methyl methyl-arylphosphinates (6) with HClO4. Scheme 4. Hydrolysis of different methyl methyl-arylphosphinates (66)) withwith HClOHClO44. The hydrolysis of p-nitrophenyl diphenylphosphinate (8) under acid catalysis was The hydrolysis of p-nitrophenyl-nitrophenyl diphenylphosphinatediphenylphosphinate ( 8) under acidacid catalysiscatalysis waswas also studied (Scheme 5) [36]. The rate constant was determined at different acid concen- also studied (Scheme 55))[ [36].36]. The rate consta constantnt was determined at different acid concentrations in a dioxane–water mixture to ensure homogeneity. There is a maximum rate at trations in in a a dioxane–water dioxane–water mixture mixture to to ensure ensure homogeneity. homogeneity. There There is isa maximum a maximum rate rate at 1.5 M HClO4. In more concentrated solutions, the acidic inhibition of the hydrolysis was 1.5at 1.5 M MHClO HClO4. In4. more In more concentrated concentrated solutions, solutions, the ac theidic acidic inhibition inhibition of the of hydrolysis the hydrolysis was observed. wasobserved. observed.

Scheme 5. Hydrolysis of p-nitrophenyl diphenylphosphinate (8) underunder acidacid catalysis.catalysis. Scheme 5. Hydrolysis of p-nitrophenyl diphenylphosphinate (8) under acid catalysis. There were cases when alkaline hydrolysis proved to be slow at room temperature, There were cases when alkaline hydrolysis proved to be slow at room temperature, but at higher temperatures it was too harsh forfor sensitivesensitive substrates.substrates. In these cases, acidic but at higher temperatures it was too harsh for sensitive substrates. In theseβ cases, acidic hydrolysis is more favorable. A good example is the acidic hydrolysis hydrolysis of a β-carboxamido--carboxamido- hydrolysis is more favorable. A good example is the acidic hydrolysis of a β-carboxamido- substituted phosphinic acid acid ester ester ( 10),), as as this is a rapid and gentle way to provideprovide thethe Molecules 2021, 26substitutedcorresponding, x FOR PEER REVIEW phosphinic phosphinic acid acid ester (11 ()10 quantitatively), as this is a (Schemerapid and6)[ gentle17]. In way this particularto provide case, the 5 of 35 corresponding phosphinic acid (11) quantitatively (Scheme 6) [17]. In this particular case, correspondingtriﬂuoroacetic acidphosphinic was the acid catalyst (11) inquantitatively an aqueous medium.(Scheme 6) [17]. In this particular case, trifluoroacetic acid was the catalyst in an aqueous medium. trifluoroacetic acid was the catalyst in an aqueous medium.

Scheme 6. HydrolysisScheme of β6.-carboxamido-substituted Hydrolysis of β-carboxamido-substituted phosphinate (10 phosphinate). (10).

In the followingIn example, the following the preparation example, the of preparation bis(3-aminophenyl)phosphinic of bis(3-aminophenyl)phosphinic acid (13) acid (13) using hydrochloricusing acid hydrochloric as the catalyst acid as in the ethanol catalyst is demonstrated in ethanol is demonstrated (Scheme7)[ 84 (Scheme]. The 7) [84]. The starting bis(aniline)starting derivative bis(aniline) was derivative obtained fromwas obtained the bis-nitro from compound the bis-nitro by compound reduction. by reduction. The exact conditionsThe exact were conditions not reported. were not reported. α-Aminophosphinic acids and their derivatives form an important group due to their synthetic and medicinal interest. The hydrolysis of phosphinates 14 using cc. HCl (Scheme8) [85] or HBr/AcOH [86] provided optically active α-aminophosphinic acids (15). The hydrolysis of β-aminophosphinates (16) was performed using hydrochloric acid at the boiling point (Scheme9)[ 87]. To 3 g substrate, 20 mL cc. HCl was added, and the mixture was stirred at reﬂux for 1.5–4 h. The hydrolysis of a GABAB antagonist ethyl phosphinate (18) was performed by applying cc. HCl at 100 ◦C for 24 h (Scheme 10)[6]. Scheme 7. Preparation of bis(3-aminophenyl) (13) phosphinic acid using hydrochloric acid as the catalyst.

α-Aminophosphinic acids and their derivatives form an important group due to their synthetic and medicinal interest. The hydrolysis of phosphinates 14 using cc. HCl (Scheme 8) [85] or HBr/AcOH [86] provided optically active α-aminophosphinic acids (15).

Scheme 8. Synthesis of α-aminophosphinic acid (15).

The hydrolysis of β-aminophosphinates (16) was performed using hydrochloric acid at the boiling point (Scheme 9) [87]. To 3 g substrate, 20 mL cc. HCl was added, and the mixture was stirred at reflux for 1.5–4 h.

Scheme 9. Hydrolysis of β-aminophosphinates (16).

The hydrolysis of a GABAB antagonist ethyl phosphinate (18) was performed by applying cc. HCl at 100 °C for 24 h (Scheme 10) [6].

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Scheme 6. Hydrolysis of β-carboxamido-substituted phosphinate (10).

In the following example, the preparation of bis(3-aminophenyl)phosphinic acid (13)

using hydrochloric acid as the catalyst in ethanol is demonstrated (Scheme 7) [84]. The startingScheme 6.bis(aniline) Hydrolysis derivativeof β-carboxamido-substituted was obtained from phosphinate the bis-nitro (10). compound by reduction. The exact conditions were not reported. In the following example, the preparation of bis(3-aminophenyl)phosphinic acid (13)

using hydrochloric acid as the catalyst in ethanol is demonstrated (Scheme 7) [84]. The Scheme 6. Hydrolysis of β-carboxamido-substituted phosphinate (10). starting bis(aniline) derivative was obtained from the bis-nitro compound by reduction. The exact conditions were not reported. In the following example, the preparation of bis(3-aminophenyl)phosphinic acid (13) using hydrochloric acid as the catalyst in ethanol is demonstrated (Scheme 7) [84]. The Molecules 2021, 26, 2840 5 of 33 starting bis(aniline) derivative was obtained from the bis-nitro compound by reduction. The exact conditions were not reported. Scheme 7. Preparation of bis(3-aminophenyl) (13) phosphinic acid using hydrochloric acid as the catalyst.

α-Aminophosphinic acids and their derivatives form an important group due to their syntheticScheme 7. andPreparation medicinal of bis(3-aminophenyl) interest. The hydrolysis (13) phosphinic of phosphinates acid using 14 hy usingdrochloric cc. HCl acid (Scheme as the 8)catalyst. [85] or HBr/AcOH [86] provided optically active α-aminophosphinic acids (15).

α-Aminophosphinic acids and their derivatives form an important group due to their Schemesynthetic 7. andPreparationPreparation medicinal of ofbis(3-aminophenyl) interest. bis(3-aminophenyl) The hydrolysis (13 ()13 phosphinic) of phosphinic phosphinates acid acid using using14 hy usingdrochloric hydrochloric cc. HCl acid (Scheme acidas the as catalyst. the8) [85] catalyst. or HBr/AcOH [86] provided optically active α-aminophosphinic acids (15). α-Aminophosphinic acids and their derivatives form an important group due to their synthetic and medicinal interest. The hydrolysis of phosphinates 14 using cc. HCl (Scheme 8) [85] or HBr/AcOH [86] provided optically active α-aminophosphinic acids (15).

Scheme 8. Synthesis of α-aminophosphinic acid (15).

The hydrolysis of β-aminophosphinates (16) was performed using hydrochloric acid

at the boiling point (Scheme 9) [87]. To 3 g substrate, 20 mL cc. HCl was added, and the Scheme 8. Synthesis of α-aminophosphinic acid (15). mixtureScheme 8. was Synthesis stirred of at α -aminophosphinicreflux for 1.5–4 h. acid (15).

The hydrolysis of β-aminophosphinates (16) was performed using hydrochloric acid

at the boiling point (Scheme 9) [87]. To 3 g substrate, 20 mL cc. HCl was added, and the Scheme 8. Synthesis of α-aminophosphinic acid (15). mixture was stirred at reflux for 1.5–4 h. The hydrolysis of β-aminophosphinates (16) was performed using hydrochloric acid at the boiling point (Scheme 9) [87]. To 3 g substrate, 20 mL cc. HCl was added, and the mixture was stirred at reflux for 1.5–4 h. Molecules 2021, 26, x FOR PEER REVIEW 6 of 35 Scheme 9. Hydrolysis of β-aminophosphinates-aminophosphinates ( 16).

The hydrolysis of a GABAB antagonist ethyl phosphinate (18 ) was performed by applying cc. HCl at 100 °C for 24 h (Scheme 10) [6]. Scheme 9. Hydrolysis of β-aminophosphinates (16).

The hydrolysis of a GABAB antagonist ethyl phosphinate (18 ) was performed by ap- Schemeplying cc 9.. HydrolysisHCl at 100 of °C β -aminophosphinatesfor 24 h (Scheme 10) (16 [6].).

The hydrolysis of a GABAB antagonist ethyl phosphinate (18) was performed by applying cc. HCl at 100 °C for 24 h (Scheme 10) [6].

Scheme 10. Preparation of GABA antagonist phosphinic acid (19) using hydrochloric acid. Scheme 10. Preparation of GABAB antagonist phosphinic acid (19) using hydrochloric acid. Natchev and co-workers investigated the acidic and enzymatic hydrolysis of phos- Natchev and co-workers investigated the acidic and enzymatic hydrolysis of phosphoryl analogues of glycine [61]. While the acidic hydrolysis was performed using 15–20% phoryl analogues of glycine [61]. While the acidic hydrolysis was performed using 15– acid at reﬂux for 6–7 h to afford the corresponding phosphinic acid (21) at a yield of 94%, 20% acid at reflux for 6–7 h to afford the corresponding phosphinic acid (21) at a yield of the enzymatic variation carried out using α-chymotrypsin under milder conditions (37 ◦C 94%, the enzymatic variation carried out using α-chymotrypsin under milder conditions for 6 h) gave the acid quantitatively (Scheme 11). (37 °C for 6 h) gave the acid quantitatively (Scheme 11). During the preparation of β-functionalized hydroxymethylphosphinic acid derivatives (22), double hydrolysis took place at a temperature of 80 ◦C in 3 h. In this case, 15 equivalents of 35% hydrochloric acid were used, which may be regarded as a large excess (Scheme 12)[88].

Scheme 11. Acidic and enzymatic hydrolysis of a glycine analogue phosphinate (20).

Scheme 12. Preparation of a β-functionalized hydroxymethylphosphinic acid derivative (23).

Dennis and co-workers investigated the hydrolyses of different saturated and unsaturated cyclic phosphinates, along with their open chain analogues under acidic conditions (Figure 2) [89]. They compared the rate constants of similar derivatives, and found the following ratios: kA/kD 1; kB/kE 1; kC/kF 3. These results are surprising, as the hydrolysis of cyclic phosphonates and phosphates is generally much faster than that of their open- chain analogues.

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Scheme 10. Preparation of GABAB antagonist phosphinic acid (19) using hydrochloric acid.

Natchev and co-workers investigated the acidic and enzymatic hydrolysis of phosphoryl analogues of glycine [61]. While the acidic hydrolysis was performed using 15– 20% acid at reflux for 6–7 h to afford the corresponding phosphinic acid (21) at a yield of Scheme 10. Preparation of GABAB antagonist phosphinic acid (19) using hydrochloric acid. 94%, the enzymatic variation carried out using α-chymotrypsin under milder conditions (37 °C for 6 h) gave the acid quantitatively (Scheme 11). Natchev and co-workers investigated the acidic and enzymatic hydrolysis of phosphoryl analogues of glycine [61]. While the acidic hydrolysis was performed using 15– 20% acid at reflux for 6–7 h to afford the corresponding phosphinic acid (21) at a yield of Molecules 2021, 26, 2840 6 of 33 94%, the enzymatic variation carried out using α-chymotrypsin under milder conditions (37 °C for 6 h) gave the acid quantitatively (Scheme 11).

Scheme 11. Acidic and enzymatic hydrolysis of a glycine analogue phosphinate (20).

During the preparation of β-functionalized hydroxymethylphosphinic acid derivatives (22), double hydrolysis took place at a temperature of 80 °C in 3 h. In this case, 15 equivalents of 35% hydrochloric acid were used, which may be regarded as a large excess Scheme 11. Acidic and enzymatic hydrolysis of a glycine analogue phosphinate (20). (SchemeScheme 11. 12)Acidic [88]. and enzymatic hydrolysis of a glycine analogue phosphinate (20). During the preparation of β-functionalized hydroxymethylphosphinic acid derivatives (22), double hydrolysis took place at a temperature of 80 °C in 3 h. In this case, 15 equivalents of 35% hydrochloric acid were used, which may be regarded as a large excess (Scheme 12) [88].

Scheme 12. PreparationPreparation of a β-functionalized-functionalized hydroxymethylp hydroxymethylphosphinichosphinic acid derivative ( 23).

Dennis and co-workersco-workers investigatedinvestigated the the hydrolyses hydrolyses of of different different saturated saturated and and unsatu- un- saturatedrated cyclic cyclic phosphinates, phosphinates, along along with with their their open open chain chain analogues analogues under under acidic acidic conditions condi-

tions(Figure (Figure2)[ 89 2)]. [89]. They They compared compared the rate the constantsrate constants of similar of similar derivatives, derivatives, and and found found the Molecules 2021, 26, x FOR PEER REVIEW 7 of 35 followingScheme 12. ratios:Preparation kA/k ofD a1; β-functionalized kB/kE 1; kC/k hydroxymethylpF 3. These resultshosphinic are surprising, acid derivative as the (23 hydrol-). the following ratios: kA/kD 1; kB/kE 1; kC/kF 3. These results are surprising, as the hydrolysis Molecules 2021, 26, x FOR PEER REVIEWysis of cyclic phosphonates and phosphates is generally much faster than that of7 their of 35 of cyclic phosphonates and phosphates is generally much faster than that of their openopen-chainDennis analogues. and co-workers investigated the hydrolyses of different saturated and un- chain analogues. saturated cyclic phosphinates, along with their open chain analogues under acidic conditions (Figure 2) [89]. They compared the rate constants of similar derivatives, and found the following ratios: kA/kD 1; kB/kE 1; kC/kF 3. These results are surprising, as the hydrolysis of cyclic phosphonates and phosphates is generally much faster than that of their open- chain analogues.

Figure 2. Cyclic and acyclic phosphinate pairs studied. Figure 2. Cyclic and acyclic phosphinatephosphinate pairs studied. The most general procedure to prepare phosphinicphosphinic acids fromfrom theirtheir estersesters involvesinvolves The most general procedure to prepare phosphinic acids from their esters involves Cρ the use of a a concentrated concentrated HCl HCl solution solution at at reflux. reﬂux. Different Different GABA GABACantagonists,ρ antagonists, such such as as1- the use of a concentrated HCl solution at reflux. Different GABACρ antagonists, such as 1- 1-hydroxyphospholanehydroxyphospholane oxide oxide 2525, were, were prepared prepared by by hydrolysis hydrolysis with with hydrochloric hydrochloric acid acid [7]. [7]. Tohydroxyphospholane 0.500.50 mmolmmol cycliccyclic esterester oxide 2424 ,,25 22 , mLmL were HClHCl prepared waswas added,added, by hydrolysis andand thethe mixturemixture with hydrochloric waswas reﬂuxedrefluxed acid forfor 5[7].5 hh (SchemeTo 0.50 mmol 1313).). cyclic ester 24, 2 mL HCl was added, and the mixture was refluxed for 5 h (Scheme 13).

Scheme 13. Preparation of GABACρ antagonistantagonist 2525 inin the the presence presence of of aqueous aqueous HCl HCl acid. acid. Scheme 13. Preparation of GABACρ antagonist 25 in the presence of aqueous HCl acid. In our our research research group, group, the the hydrolysis hydrolysis of of a aseries series of ofcyclic cyclic phosphinates phosphinates (26 ()26 was) was in- investigatedvestigatedIn our (Scheme research (Scheme 14) group, 14 [90].)[90 the].First, First, hydrolysis we we wished wished of ato toseries explore explore of cyclicthe the optimal optimal phosphinates reaction reaction ( 26conditions, conditions,) was in- vestigatedincluding the (Scheme reaction 14) time, [90]. acid First, concentration, we wished to and explore the necessary the optimal amount reaction of hydrochloric conditions, acid.including It was the found reaction that time, for the acid hy concentration,drolysis of 1.9 andmmol the phosphinate necessary amount (26), the of use hydrochloric of 0.5 mL ccacid.. HCl It wasand found1 mL waterthat for was the optimal, hydrolysis along of 1.9 with mmol a reaction phosphinate time of (26 6 ),h. the Interestingly, use of 0.5 mL in thecc. HCl case and of the 1 mL hydrolysis water was of optimal,unsaturated along cyclic with phosphinates, a reaction time these of 6 compounds h. Interestingly, under- in wentthe case isomerization of the hydrolysis as well. of The unsaturated results are cyclic summarized phosphinates, in Table these 1. compounds underwent isomerization as well. The results are summarized in Table 1.

Scheme 14. Hydrolysis of saturated and unsaturated cyclic phosphinates (26). Scheme 14. Hydrolysis of saturated and unsaturated cyclic phosphinates (26).

Molecules 2021, 26, x FOR PEER REVIEW 7 of 35

Figure 2. Cyclic and acyclic phosphinate pairs studied.

The most general procedure to prepare phosphinic acids from their esters involves

the use of a concentrated HCl solution at reflux. Different GABACρ antagonists, such as 1- hydroxyphospholane oxide 25, were prepared by hydrolysis with hydrochloric acid [7]. To 0.50 mmol cyclic ester 24, 2 mL HCl was added, and the mixture was refluxed for 5 h (Scheme 13).

Scheme 13. Preparation of GABACρ antagonist 25 in the presence of aqueous HCl acid. Molecules 2021, 26, 2840 7 of 33 In our research group, the hydrolysis of a series of cyclic phosphinates (26) was investigated (Scheme 14) [90]. First, we wished to explore the optimal reaction conditions, including the reaction time, acid concentration, and the necessary amount of hydrochloric acid. It was found that for the hy hydrolysisdrolysis of 1.9 mmol phosphinate (26), the use of 0.5 mL cc. HCl andand 11 mLmL waterwater was was optimal, optimal, along along with with a reactiona reaction time time of 6of h. 6 Interestingly,h. Interestingly, in the in thecase case of the of hydrolysisthe hydrolysis of unsaturated of unsaturated cyclic cyclic phosphinates, phosphinates, these these compounds compounds underwent under- wentisomerization isomerization as well. as Thewell. results The results are summarized are summarized in Table in 1Table. 1.

Molecules 2021, 26, x FOR PEER REVIEW 8 of 35 Molecules 2021, 26, x FOR PEER REVIEW Molecules 2021, 26, x FOR PEER REVIEW 8 of 35 8 of 35 Molecules 2021, 26, x FOR PEER REVIEW 8 of 35 Molecules 2021, 26, x FOR PEER REVIEW 8 of 35 Molecules 2021, 26, x FOR PEER REVIEW 8 of 35

Scheme 14. Hydrolysis of saturated and unsaturatedunsaturated cyclic phosphinates (26). Table 1. Experimental data of the hydrolysis of unsaturated and saturated cyclic phosphinates. Table 1. Experimental data ofTable the hydrolysis 1. Experimental of unsaturated data of theand hydrolysis saturated ofcyclic unsaturated phosphinates. and saturated cyclic phosphinates. Table 1. Experimental data of the hydrolysis of unsaturated and saturated cyclic phosphinates. Table 1. ExperimentalTable 1. data Experimental of the hydrolysis data of ofthe unsaturated hydrolysis andof un saturatedsaturated cyclic and saturated phosphinates. cyclic phosphinates. Table 1. Experimental data of the hydrolysisComposition of unsaturated ofand Product saturated (%) cyclic phosphinates. Compound Compositiont (h) of Product (%)Composition of Product (%) Yield (%) Compound tCompound (h) t (h) Composition of ProductYield (%) (%) Yield (%) Compound 2-Phospholenet (h) Composition2-Phospholene3-Phospholene ofComposition Product (%) of Product3-Phospholene (%) Yield (%) CompoundCompound t (h) t (h) 2-Phospholene 3-PhospholeneYield (%) Yield (%) 2-Phospholene2-Phospholene 3-Phospholene 3-Phospholene

3 79 3 79 21 85 21 85 3 79 21 85 33 7979 21 85 21 85

6 90 6 90 10 84 10 84 66 9090 10 84 10 84 6 90 10 84

6 21 6 21 73 86 73 86 66 2121 73 86 73 86 6 21 73 86

8 88 – –– 82 82 82 8 – 82 8 – 82

10 1010 – –– 80 80 80 10 – 80 10 – 80

After exploring the optimumAfter conditions, exploring the the method optimum was conditions, extended tothe the method hydrolysis was extended to the hydrolysis After exploring the optimumAfter conditions, exploring the the method optimum was conditions, extended tothe the method hydrolysis was extended to the hydrolysis of other esters, and the kineticsof other wereAfter esters, alsoexploring investigated.and the the kinetics optimum Figure were conditions,3 demonstrates also investigated. the method the order Figure was of 3 extended demonstrates to the the hydrolysis order of of other esters, and the kineticsof other wereAfter esters, alsoexploring investigated.and the the kinetics optimum Figure were conditions, 3 demonstratesalso investigated. the method the orderFigure was of 3 extended demonstrates to the the hydrolysis order of reactivity observed under thereactivityof other above-mentioned esters, observed and theunder conditions kinetics the ab wereove-mentioned [90]. also investigated. conditions Figure [90]. 3 demonstrates the order of reactivity observed under thereactivityof other above-mentioned esters, observed and theunder conditions kinetics the ab were ove-mentioned[90]. also investigated. conditions Figure [90]. 3 demonstrates the order of reactivity observed under the above-mentioned conditions [90].

Figure 3. Reactivity order for different cyclic phosphinate derivatives. Figure 3. Reactivity order for Figuredifferent 3. cyReactivityclic phosphinate order for derivatives. different cy clic phosphinate derivatives. Figure 3. Reactivity order forFigure different 3. cyclicReactivity phosphinate order for derivatives. different cyclic phosphinate derivatives. Figure 3. Reactivity order for different cyclic phosphinate derivatives. The hydrolyses were also carried out under microwave (MW) conditions. In this case, The hydrolyses were also carriedThe hydrolyses out under were microwave also carried (MW) out conditions. under microwave In this case, (MW) conditions. In this case, p-toluenesulfonic acid (PTSA)p-toluenesulfonic wasThe usedhydrolyses as the acid werecatalyst (PTSA) also in carriedwas order used toout avoidas under the the catalyst microwave corrosion in order (MW) of to conditions. avoid the corrosion In this case, of thep-toluenesulfonic reactor (Scheme acid 15) (PTSA) [90]. It wasis important used as theto note catalyst that duein order to the to beneficial avoid the effect corrosion of MW of the reactor (Scheme 15) [90].thep-toluenesulfonic It reactoris important (Scheme to acid note 15) (PTSA) [90].that Itdue wasis importantto usedthe beneficial as tothe note catalyst effect that dueofin MWorder to the to beneficial avoid the effect corrosion of MW of irradiation, the reaction timesirradiation,the reactor were shorter (Scheme the reaction th 15)an they[90]. times Itwere iswere important in shorterthe case to th noteofan conventional theythat duewere to in the the beneficial case of conventionaleffect of MW heating.irradiation, the reaction times were shorter than they were in the case of conventional heating. heating.irradiation, the reaction times were shorter than they were in the case of conventional heating.

Scheme 15. MW-assisted hydrolysis of alkoxyphospholene oxides (26A) in the presence of PTSA. Scheme 15. MW-assisted hydrolysisScheme of 15. alkoxyphospholene MW-assisted hydrolysis oxides of(26A alkoxyphospholene) in the presence of oxides PTSA. (26A ) in the presence of PTSA. Scheme 15. MW-assisted hydrolysis of alkoxyphospholene oxides (26A) in the presence of PTSA. Scheme 15. MW-assisted hydrolysis of alkoxyphospholene oxides (26A) in the presence of PTSA.

Molecules 2021, 26, x FOR PEER REVIEW 8 of 35

Table 1. Experimental data of the hydrolysis of unsaturated and saturated cyclic phosphinates.

Composition of Product (%) Compound t (h) Yield (%) 2-Phospholene 3-Phospholene

3 79 21 85

6 90 10 84

6 21 73 86

8 – 82

10 – 80

After exploring the optimum conditions, the method was extended to the hydrolysis of other esters, and the kinetics were also investigated. Figure 3 demonstrates the order of reactivity observed under the above-mentioned conditions [90].

Molecules 2021, 26, 2840 8 of 33 Figure 3. Reactivity order for different cyclic phosphinate derivatives.

The hydrolyses hydrolyses were were also also carried carried out out under under microwave microwave (MW) (MW) conditions. conditions. In this In case, this pcase,-toluenesulfonicp-toluenesulfonic acid (PTSA) acid (PTSA) was used was as used the catalyst as the catalyst in order in to order avoid to the avoid corrosion the cor- of therosion reactor of the (Scheme reactor 15) (Scheme [90]. It is15 important)[90]. It is to important note that due to note to the that beneficial due to the effect beneﬁcial of MW irradiation,effect of MW the irradiation, reaction times thereaction were shorter times th werean they shorter were than in the they case were of inconventional the case of heating.conventional heating.

Molecules 2021, 26, x FOR PEER REVIEW 9 of 35

Scheme 15. MW-assisted hydrolysis of alkoxyphospholene oxides (26A26A)) inin thethe presencepresence ofof PTSA.PTSA.

The acidic hydrolysis of acyclic esters, such as diphenylphosphinates (30), was also studied under under conventional conventional heating heating and and microwave microwave irradiation irradiation (Scheme (Scheme 16) 16 [91].)[91 The]. Thetra- ditionaltraditional hydrolysis hydrolysis was was performed performed using using three three equivalents equivalents of diluted of diluted hydrochloric hydrochloric acid foracid 3–6.5 for 3–6.5h. In h.the In other the otherseriesseries of expe ofriments experiments comprising comprising MW-assisted MW-assisted hydrolyses, hydrolyses, p-toluenesulfonicp-toluenesulfonic acid acidwas wasused used as the as thecatalyst. catalyst. The Theamount amount of the of thecatalyst catalyst was was decreased decreased to 0.1to 0.1equivalents. equivalents. At 160 At 160°C, complete◦C, complete hydrolysis hydrolysis occurred occurred in 2–6.5 in 2–6.5 h, and h, at and 180 at °C 180 in ◦0.5–2C in h.0.5–2 The h. pseudo–first-order The pseudo–ﬁrst-order rate consta rate constantsnts obtained obtained are listed are listedin Table in Table2. 2.

Scheme 16. 16. AcidicAcidic hydrolysis hydrolysis of ofdiphenylphosphinates diphenylphosphinates (30) (under30) under conventional conventional heating heating and MW and irradiation.MW irradiation.

Table 2. Pseudo–first-order rate constants (kΔ and kMW) obtained for the thermal HCl-catalyzed Table 2. Pseudo–ﬁrst-order rate constants (k∆ and kMW) obtained for the thermal HCl-catalyzed and andMW-assisted MW-assisted PTSA-catalyzed PTSA-catalyzed hydrolyses. hydrolyses.

−1 −1 Entry R kΔ (h ) −1 kMW (h −)1 Entry R k∆ (h ) kMW (h ) 1 Me 1.36 1.52 1 Me 1.36 1.52 2 2Et Et 0.62 0.62 0.86 0.86 3 3 nPr nPr 0.62 0.62 – – 4 4 iPr iPr 1.601.60 1.92 1.92 n 5 5 nBu Bu0.57 0.57 – –

2.2. Acidic Acidic Hydrolysis of Phosphonates The hydrolysis of phosphonates is a widelywidely applied method. Due to the two ester groups, these hydrolyses take place in two st stepseps in a consecutive manner. Most often, the aqueous solution ofof hydrochlorichydrochloric acidacid was was applied applied as as the the medium, medium, and and after after the the hydrolysis, hydrolysis,the the water water was was removed removed by distillation.by distillation. Occasionally, Occasionally, HBr HBr was was also also used used in thein the hydrolysis hydrolysisof phosphonates of phosphonates [21]. [21]. Methylphosphonic acid (32), which is known as a flame retardant, may be prepared by the acidic hydrolysis of dimethyl methylphosphonate (31) (Scheme 17) [18].

Scheme 17. Preparation of methylphosphonic acid (32) by acidic hydrolysis.

The effect of the alkyl group of dialkyl phosphonates was investigated in acid- and base-catalyzed hydrolyses. It was found that during acid catalysis, the isopropyl derivative was hydrolyzed faster than the methyl ester, but under basic conditions, the reaction of the methyl ester was 1000-fold faster than that of the isopropyl derivative [92].

Molecules 2021, 26, x FOR PEER REVIEW 9 of 35

The acidic hydrolysis of acyclic esters, such as diphenylphosphinates (30), was also studied under conventional heating and microwave irradiation (Scheme 16) [91]. The tra- ditional hydrolysis was performed using three equivalents of diluted hydrochloric acid for 3–6.5 h. In the other series of experiments comprising MW-assisted hydrolyses, p-toluenesulfonic acid was used as the catalyst. The amount of the catalyst was decreased to 0.1 equivalents. At 160 °C, complete hydrolysis occurred in 2–6.5 h, and at 180 °C in 0.5–2 h. The pseudo–first-order rate constants obtained are listed in Table 2.

Scheme 16. Acidic hydrolysis of diphenylphosphinates (30) under conventional heating and MW irradiation.

Table 2. Pseudo–first-order rate constants (kΔ and kMW) obtained for the thermal HCl-catalyzed and MW-assisted PTSA-catalyzed hydrolyses.

Entry R kΔ (h−1) kMW (h−1) 1 Me 1.36 1.52 2 Et 0.62 0.86 3 nPr 0.62 – 4 iPr 1.60 1.92 5 nBu 0.57 –

2.2. Acidic Hydrolysis of Phosphonates The hydrolysis of phosphonates is a widely applied method. Due to the two ester groups, these hydrolyses take place in two steps in a consecutive manner. Most often, the Molecules 2021, 26, 2840 9 of 33 aqueous solution of hydrochloric acid was applied as the medium, and after the hydrolysis, the water was removed by distillation. Occasionally, HBr was also used in the hydrolysis of phosphonates [21]. Methylphosphonic acid ( 32), which is known as a ﬂameflame retardant, may be prepared by the acidic hydrolysis of dimethyl methylphosphonate (31)) (Scheme(Scheme 1717))[ [18].18].

Scheme 17. Preparation of methylphosphonic acid (32) by acidic hydrolysis.

Molecules 2021, 26, x FOR PEER REVIEW The effect of the alkyl group of dialkyl phosphonates was investigated in acid-10 andof 35 Molecules 2021, 26, x FOR PEER REVIEW The effect of the alkyl group of dialkyl phosphonates was investigated in acid-10 andof 35 base-catalyzed hydrolyses.hydrolyses. ItIt waswas found found that that during during acid acid catalysis, catalysis, the the isopropyl isopropyl derivative deriva- wastive was hydrolyzed hydrolyzed faster faster than than the methyl the methyl ester, es butter, under but under basic conditions,basic conditions, the reaction the reaction of the ofmethyl theOur methyl ester research was ester 1000-fold group was 1000-fold investigated faster thanfaster the that than preparation of that the isopropylof the of isopropyl arylphosphonic derivative derivative [92 acids]. [92]. (34 ) by re- fluxingOur the researchresearch corresponding groupgroup investigated investigated phosphonates the the preparation (preparation33) with an of of arylphosphonicexcess arylphosphonic (six equivalents) acids acids (34 )(of34 by )hydro- reﬂux-by re- chloricingfluxing the acid correspondingthe correspondingfor 12 h (Scheme phosphonates phosphonates 18) [93]. (33) with(33) with an excess an excess (six equivalents) (six equivalents) of hydrochloric of hydro- acidchloric for acid 12 h for (Scheme 12 h (Scheme 18)[93]. 18) [93].

Scheme 18. Acidic hydrolysis of dialkyl arylphosphonates (33). Scheme 18. Acidic hydrolysis of dialkyldialkyl arylphosphonates (33).). Depending on the substituents, the phosphonic acids were obtained in yields of 71– Depending on the substituents, the phosphonic acids were obtained in yields of 93% [93].Depending However, on thea reflux substituents, with concentrated the phosphonic hydrochloric acids were acid obtained for 12 h incannot yields be of con- 71– 71–93% [93]. However, a reﬂux with concentrated hydrochloric acid for 12 h cannot be sidered93% [93]. to However, be a “gentle” a reflux method. with concentrated hydrochloric acid for 12 h cannot be con- considered to be a “gentle” method. sideredWe toalso be astudied “gentle” the method. hydrolysis of various arylphosphonates (35): phenylphospho- We also studied the hydrolysis of various arylphosphonates (35): phenylphosphonates natesWe and also their studied derivatives the hydrolysis containing of a various4-methyl arylphosphonates or a 4-acetyl group (35 in): phenylphospho-the phenyl ring. andnates their and derivativestheir derivatives containing containing a 4-methyl a 4-methyl or a 4-acetylor a 4-acetyl group group in the in phenyl the phenyl ring. ring. The Thereactions reactions were were carried carried out out at the at the optimum optimum conditions conditions found found for for the the hydrolysis hydrolysis of cyclicof cy- clicThe phosphinates reactions were (Scheme carried 19) out [94]. at the In optimummost of the conditions cases, the found reaction for proceeded the hydrolysis according of cy- phosphinatesclic phosphinates (Scheme (Scheme 19)[ 19)94]. [94]. In most In most of theof the cases, cases, the the reaction reaction proceeded proceeded according according to to the AAc2 mechanism, but in the case of the benzyl and isopropyl ester, the AAl1 mecha- the AAc2 mechanism, but in the case of the benzyl and isopropyl ester, the AAl1 mechanism nismto the was AAc 2substantiated. mechanism, but in the case of the benzyl and isopropyl ester, the AAl1 mecha- wasnism substantiated. was substantiated.

Scheme 19. Acidic hydrolysis of di dialkylalkyl arylphosphonates (35) under the optimum conditions. Scheme 19. Acidic hydrolysis of dialkyl arylphosphonates (35) under the optimum conditions. The consecutive reaction steps were characterized by pseudo–first-order rate constants.The One consecutive can see that reaction the cleavage steps wereof the charac secondterized P-OC bybond pseudo–first-order was the slower process rate con- in eachstants. case, One suggesting can see that that the the cleavage latter is of the the rate-determining second P-OC bond step was (Table the 3). slower process in each case, suggesting that the latter is the rate-determining step (Table 3).

Table 3. Pseudo–first-order rate constants (kΔ and kMW) obtained for the thermal HCl-catalyzed andTable MW-assisted 3. Pseudo–first-order PTSA-catalyzed rate constants hydrolyses. (kΔ and kMW) obtained for the thermal HCl-catalyzed and MW-assisted PTSA-catalyzed hydrolyses. R2 R1 k1 (h−1) k2 (h−1) tcompl Yield (%) R2 R1 k1 (h−1) k2 (h−1) tcompl Yield (%) Me H 2.67 0.70 5.5 h 95 Me H 2.67 0.70 5.5 h 95 Et H 0.88 0.27 9.5 h 90 Et H 0.88 0.27 9.5 h 90 iPr H 2.08 1.33 4.5 h 99 iPr H 2.08 1.33 4.5 h 99 Bn H 23.8 9.36 45 min 80 Bn H 23.8 9.36 45 min 80 Et Me 0.86 0.16 17.5 h 87 Et Me 0.86 0.16 17.5 h 87 Et MeC(O) 0.90 0.35 8.5 h 86 Et MeC(O) 0.90 0.35 8.5 h 86

Molecules 2021, 26, 2840 10 of 33

The consecutive reaction steps were characterized by pseudo–ﬁrst-order rate constants. One can see that the cleavage of the second P-OC bond was the slower process in each case, suggesting that the latter is the rate-determining step (Table3).

Table 3. Pseudo–ﬁrst-order rate constants (k∆ and kMW) obtained for the thermal HCl-catalyzed and MW-assisted PTSA-catalyzed hydrolyses.

2 1 −1 −1 R R k1 (h ) k2 (h ) tcompl Yield (%) Me H 2.67 0.70 5.5 h 95 Et H 0.88 0.27 9.5 h 90 iPr H 2.08 1.33 4.5 h 99 Bn H 23.8 9.36 45 min 80 Molecules 2021,, 26,, xx FORFOR PEERPEER REVIEWREVIEW Et Me 0.86 0.16 17.5 h 87 11 of 35 Et MeC(O) 0.90 0.35 8.5 h 86

Based onon thethe experimentalexperimental data, data, the the overall overall reactivity reactivity order order of theof the different different derivatives deriva- 2 Based1 on the experimental data, the overall reactivity order of the different deriva- (R /R )2 is the1 following: tives (R2/R1) is the following: i Bn/H >> iPr/H ~Me/H > Et/C(O)Me > Et/H > Et/Me. Bn/HBn/H >> i >>Pr/H Pr/H ~Me/H ~Me/H > > Et/C(O)Me Et/C(O)Me > > Et/HEt/H > Et/Me.

Biologically important α-hydroxyphosphonic acids acids ( 38,, 40) werewere preparedprepared byby thethe prolongedprolonged (1–2 days) days) heating heating of of various various hydr hydroxyphosphonatesoxyphosphonates with with a large a large excess excess of hy- of hydrochloricdrochloric acid acid (Scheme (Scheme 20) 20 [95].)[95 ].

Scheme 20.20. Acidic hydrolysis ofof biologicalbiological activeactive αα-hydroxyphosphonates-hydroxyphosphonates-hydroxyphosphonates (((3737 andandand 393939).).).

α-Hydroxyphosphonic-Hydroxyphosphonic acidsacids ((42)) werewere preparedprepared byby thethe hydrochlorichydrochloric acid-promotedacid-promoted hydrolysis ofof hydroxyphosphonateshydroxyphosphonates ((4141)) (Scheme(Scheme 2121))[ [96].96]. TheThe hydrolysishydrolysis waswas performedperformed ◦ using 66 NN HClHCl inin dioxane-waterdioxane-water atat 8080 °CC for 33 days.days.

OH 80 °C, 3 days OH O O O 6 N HCl O P OR P OH X dioxane-H2O X OR 2 OH 42 41 42 85% R = Menthyl 85% X=OMe,H X=OMe,H Scheme 21.21. Preparation of biologicallybiologically activeactive αα-hydroxy-benzylphosphonic-hydroxy-benzylphosphonic acidsacidsacids (((4242).).). We investigated the acid-catalyzed reactions of a series of α-hydroxy-benzylphosphonates We investigated the acid-catalyzed reactions of a series of α-hydroxy-ben- (43) in order to evaluate the effect of the ester function, and the substituents in the phenyl ring zylphosphonates (43) in order to evaluate the effect of the ester function, and the substituents in the phenyl ring on the rate (Scheme 22) [97]. The reactions were performed in water with 3 equivalents of hydrochloric acid, and depending on the substituents, the completion took 2.5–9.5 h. Electron-withdrawing substituents increased the reaction rate, while electron-releasing substituents slowed downdown thethe hydrolysis.hydrolysis. TheThe experimentalexperimental andand kinetic data are summarized in Table 4, while representative concentration profiles of the hydrolyses are shown in Figure 4.

Scheme 22. Two-step acidic hydrolysis of substituted α-hydroxybenzylphosphonates-hydroxybenzylphosphonates ((43).).

Molecules 2021, 26, x FOR PEER REVIEW 11 of 35

Based on the experimental data, the overall reactivity order of the different derivatives (R2/R1) is the following: Bn/H >> iPr/H ~Me/H > Et/C(O)Me > Et/H > Et/Me.

Biologically important α-hydroxyphosphonic acids (38, 40) were prepared by the prolonged (1–2 days) heating of various hydroxyphosphonates with a large excess of hydrochloric acid (Scheme 20) [95].

Scheme 20. Acidic hydrolysis of biological active α-hydroxyphosphonates (37 and 39).

α-Hydroxyphosphonic acids (42) were prepared by the hydrochloric acid-promoted hydrolysis of hydroxyphosphonates (41) (Scheme 21) [96]. The hydrolysis was performed using 6 N HCl in dioxane-water at 80 °C for 3 days.

OH 80 °C, 3 days OH O 6 N HCl O P OR P OH X dioxane-H O X OR 2 OH 41 42 R = Menthyl 85% X=OMe,H Scheme 21. Preparation of biologically active α-hydroxy-benzylphosphonic acids (42).

Molecules 2021, 26, 2840 11 of 33 We investigated the acid-catalyzed reactions of a series of α-hydroxy-benzylphosphonates (43) in order to evaluate the effect of the ester function, and the substituents in the phenyl ring on the rate (Scheme 22) [97]. The reactions were performed in onwater the with rate (Scheme3 equivalents 22) [97 ].of Thehydrochloric reactions wereacid, performedand depending in water on withthe substituents, 3 equivalents the of hydrochloriccompletion took acid, 2.5–9.5 and depending h. Electron-withdrawi on the substituents,ng substituents the completion increased took 2.5–9.5 the reaction h. Electron- rate, withdrawingwhile electron-releasing substituents substituents increased the slowed reaction down rate, the while hydrolysis. electron-releasing The experimental substituents and slowedkinetic downdata are the summarized hydrolysis. Thein Table experimental 4, while representative and kinetic data concentr are summarizedation profiles in Table of the4, whilehydrolyses representative are shown concentration in Figure 4. profiles of the hydrolyses are shown in Figure4.

SchemeScheme 22.22. Two-stepTwo-step acidicacidic hydrolysishydrolysis ofof substitutedsubstitutedα α-hydroxybenzylphosphonates-hydroxybenzylphosphonates ( 43(43).).

Table 4. Experimental and kinetic data on the hydrolysis of substituted α-hydroxybenzylphosphonates (43).

−1 −1 Entry Y R Yield (%) tr (h) k1 (h ) k2 (h ) 1 H Me 80 6.5 2.64 0.60 2 NO2 Me 82 2.5 5.18 1.24 3 Cl Me 90 5.5 3.36 0.79 4 F Me 85 6.0 3.93 0.67 5 CF3 Me 80 5.5 2.03 0.61 6 Me Me 79 8 1.64 0.31 7 H Et 82 9.5 1.03 0.35 8 NO2 Et 92 5.5 1.40 0.61 9 Cl Et 87 8.0 1.08 0.42 10 F Et 83 9.0 1.35 0.31

Figure 4. Concentration proﬁles for the components during the hydrolysis of different α- hydroxyphosphonates (43). Molecules 2021, 26, 2840 12 of 33

Molecules 2021, 26, x FOR PEER REVIEW 13 of 35 Molecules 2021, 26, x FOR PEER REVIEW Aminophosphonic acids form another important family of bioactive compounds.13 of 35 Molecules 2021, 26, x FOR PEER REVIEW 13 of 35 These species are the analogues of amino acids. The preparation of aminomethylphosphonic acid (47) by hydrolysis involved the removal of the protecting group (Scheme 23)[3].

Scheme 23. Preparation of aminomethylphosphonic acid (47). SchemeScheme 23.23. PreparationPreparation ofof aminomethylphosphonicaminomethylphosphonic acidacid ((4747).).). There is also an example for the HBr/acetic acid-catalyzed hydrolysis of aminophos- There is also an example for the HBr/aceticHBr/acetic acid-catalyzed acid-catalyzed hydrolysis hydrolysis of aminophos- phonatesThere [98]. is also In the an examplesynthesis for of thea biologic HBr/acetically relevant acid-catalyzed aminomethylene-bisphosphonic hydrolysis of aminophosphonates [[98].98]. In the synthesis of aa biologicallybiologically relevantrelevant aminomethylene-bisphosphonicaminomethylene-bisphosphonic acidphonates (49), the[98]. last In stepthe synthesis involved ofa HCl-catalyzed a biologically relevanthydrolysis aminomethylene-bisphosphonic (Scheme 24) [99]. acidacid ((4949),), thethe lastlast stepstep involvedinvolved aaa HCl-catalyzedHCl-catalyzedHCl-catalyzed hydrolysishydrolysishydrolysis (Scheme(Scheme(Scheme 24 24)24))[ [99].[99].99].

Scheme 24. Acidic hydrolysis of aminomethylene-bisphosphonate 48.. SchemeScheme 24.24. AcidicAcidic hydrolysishydrolysis ofof aminomethylene-bisphosphonateaminomethylene-bisphosphonate 4848.. Phosphonic acid analogues of certain amino acids may have significant biological Phosphonic acid analogues of certain amino acids maymay havehave significantsignificant biologicalbiological effects,Phosphonic e.g., arginine acid mimetics analogues inhibit of certain the activity amino of acids the enzymes may have responsible significant for biological the sur- effects, e.g., arginine mimetics inhibit the activity of the enzymes responsible for the sur- vivaleffects, of e.g.,parasites; arginine hence, mimetics they can inhibit be used the as activity anti-malarial of the enzymes agents [100]. responsible The corresponding for the sur- vival of parasites; hence, they can be used as anti-malarial agents [[100].100]. The corresponding compoundsvival of parasites; were obtainedhence, they by canhydrolysis be used withas anti-malarial hydrochloric agents acid [100].[100], Theor acetic corresponding acid com- compounds were obtained by hydrolysis with hy hydrochloricdrochloric acid [100], [100], or acetic acid com- binedcompounds with hydrogen were obtained bromide by hydrolysis[31]. This change with hy indrochloric the functionality acid [100], was or performed acetic acid in com- the bined with hydrogen hydrogen bromide bromide [31]. [31]. This This change change in inthe the functionality functionality was was performed performed in the in lastbined step with of thehydrogen synthesis. bromide Similar [31]. compound This changes were in preparedthe functionality from thioureidoalkane was performed phos-in the thelast laststep step of the of synthesis. the synthesis. Similar Similar compound compoundss were wereprepared prepared from thioureidoalkane from thioureidoalkane phos- phonateslast step of by the treatment synthesis. with Similar acetic compound acid and hydrochlorics were prepared acid from at reflux thioureidoalkane for 7 h [101]. phos- phosphonatesphonates by treatment by treatment with withacetic acetic acid acidand hydrochloric and hydrochloric acid acidat reflux at reflux for 7 for h [101]. 7 h [101 ]. phonatesThe hydrolysis by treatment of witha benzimidazole acetic acid and phosphonate hydrochloric50 (50 acid) was at carriedreflux for out 7 husing [101]. a 40% The hydrolysishydrolysis ofof a a benzimidazole benzimidazole phosphonate phosphonate ( ()50 was) was carried carried out out using using a 40% a HBr40% solutionHBr solutionThe at hydrolysis reflux at reflux for 10of for ha (Scheme10benzimidazole h (Scheme 25)[28 25) ].phosphonate [28]. (50) was carried out using a 40% HBrHBr solutionsolution atat refluxreflux forfor 1010 hh (Scheme(Scheme 25)25) [28].[28].

Scheme 25. HBr-catalyzed hydrolysis of a benzimidazole phosphonatephosphonate derivativederivative ((5050).). SchemeScheme 25.25. HBr-catalyzedHBr-catalyzed hydrolysishydrolysis ofof aa benzimidazolebenzimidazole phosphonatephosphonate derivativederivative ((5050).). In thethe followingfollowing example, example, the the hydrolysis hydrolysis of theof the succinic succinic acid acid derivative derivative (52) took (52) placetook In the following example, the hydrolysis of the succinic acid derivative (52) took inplace anIn autocatalyticin thean autocatalytic following manner. example, manner. The two theThe hydrolysis succinatetwo succinate functions of thefunctions succinic were were also acid also hydrolyzed derivative hydrolyzed under (52 under) took the place in an autocatalytic manner. The two succinate functions were also hydrolyzed under conditionstheplace conditions in an applied.autocatalytic applied. The intermediatesThemanner. intermediates The two may succ catalyzemayinate catalyze functions further further hydrolysis were hydrolysis also duehydrolyzed to due their to acidicunder their the conditions applied. The intermediates may catalyze further hydrolysis due to their natureacidicthe conditions nature (Scheme (Scheme applied.26)[79 ].26) The [79]. ethanolintermediates The ethanol released mayreleased was catalyze removed was removedfurther by azeotropic hydrolysis by azeotropic distillation. due distilla-to their acidic nature (Scheme 26) [79]. The ethanol released was removed by azeotropic distillation.acidic Following nature (Scheme the spread 26) [79]. of the The MW ethanol technique, released the was effect removed of irradiation by azeotropic on hydrolysis distilla- wastion.tion. also studied [20,102]. An example from the pharmaceutical ﬁeld is the synthesis of Adefovir, during which the diisopropyl ester moiety of phosphonate 54 was hydrolyzed in an acid-catalyzed manner under MW conditions (Scheme 27)[20].

Scheme 26. Autocatalytic hydrolysis of a succinic acid derivative (52). SchemeScheme 26.26. AutocatalyticAutocatalytic hydrolysishydrolysis ofof aa succinicsuccinic acidacid derivativederivative ((5252).).

Molecules 2021, 26, x FOR PEER REVIEW 13 of 35

Scheme 23. Preparation of aminomethylphosphonic acid (47).

There is also an example for the HBr/acetic acid-catalyzed hydrolysis of aminophosphonates [98]. In the synthesis of a biologically relevant aminomethylene-bisphosphonic acid (49), the last step involved a HCl-catalyzed hydrolysis (Scheme 24) [99].

Scheme 24. Acidic hydrolysis of aminomethylene-bisphosphonate 48.

Phosphonic acid analogues of certain amino acids may have significant biological effects, e.g., arginine mimetics inhibit the activity of the enzymes responsible for the sur- vival of parasites; hence, they can be used as anti-malarial agents [100]. The corresponding compounds were obtained by hydrolysis with hydrochloric acid [100], or acetic acid com- bined with hydrogen bromide [31]. This change in the functionality was performed in the last step of the synthesis. Similar compounds were prepared from thioureidoalkane phosphonates by treatment with acetic acid and hydrochloric acid at reflux for 7 h [101]. The hydrolysis of a benzimidazole phosphonate (50) was carried out using a 40% HBr solution at reflux for 10 h (Scheme 25) [28].

Scheme 25. HBr-catalyzed hydrolysis of a benzimidazole phosphonate derivative (50).

In the following example, the hydrolysis of the succinic acid derivative (52) took place in an autocatalytic manner. The two succinate functions were also hydrolyzed under

Molecules 2021, 26, 2840 the conditions applied. The intermediates may catalyze further hydrolysis due to13 their of 33 acidic nature (Scheme 26) [79]. The ethanol released was removed by azeotropic distillation.

Molecules 2021, 26, x FOR PEER REVIEW 14 of 35

Following the spread of the MW technique, the effect of irradiation on hydrolysis was also studied [20,102]. An example from the pharmaceutical field is the synthesis of was also studied [20,102]. An example from the pharmaceutical field is the synthesis of Adefovir, during which the diisopropyl ester moiety of phosphonate 54 was hydrolyzed Scheme 26. Autocatalytic hydrolysis of a succinic acidacid derivativederivative ((5252).). in an acid-catalyzed manner under MW conditions (Scheme 27) [20].

Scheme 27.27. MW-assisted acidicacidic hydrolysishydrolysis ofof thethe diisopropyldiisopropyl esterester ofof AdefovirAdefovir ((5454).).

The acidicacidic hydrolysis hydrolysis of aof series a series of alkyl of αalkyl-hydroxyimino- α-hydroxyimino-α-(p-nitrophenyl)α-(p-nitrophenyl) alkylphos- al- phonateskylphosphonates (56) revealed (56) revealed that the that reaction the reaction rate decreases rate decreases with increasing with increasing steric hindrancesteric hin- (Schemedrance (Scheme 28)[103 28)]. In [103]. addition In addition to the ester to the function, ester function, the neighbouring the neighbouring groups groups also had also a 2 2 signiﬁcanthad a significant effect oneffect the on hydrolysis, the hydrolysis, e.g., when e.g., when a tert-butyl a tert-butyl group group (R ) was (R2) replaced was replaced by a methylby a methyl substituent, substituent, a 100-fold a 100-fold reaction reaction ratewas rate observedwas observed [103]. [103].

α α Scheme 28.28. The acidicacidic hydrolysishydrolysis of of alkyl alkyl α-hydroxyimino--hydroxyimino--(αp-(-nitrophenyl)p-nitrophenyl) alkylphosphonates alkylphosphonates (56 ). (56). 3.(56 Alkaline). and Basic Hydrolysis 3.1. Alkaline and Basic Hydrolysis of Phosphinates 3. Alkaline and Basic Hydrolysis The effect of various factors on alkaline hydrolysis was investigated in a few pub- 3.1. Alkaline and Basic Hydrolysis of Phosphinates lications [104–106]. The inﬂuencing factors include the leaving ability of the departing The effect of various factors on alkaline hydrolysis was investigated in a few publi- groupThe [104 effect,105 ,of107 various,108], the factors stability on alkaline of the resultinghydrolysis intermediate was investigated [107], in the a few nature publi- of cations [104–106]. The influencing factors include the leaving ability of the departing thecations heteroatom [104–106]. connected The influencing to the phosphorus factors include atom [the106 ],leaving the solvent ability [106 of], the the departing pH [109] group [104,105,107,108], the stability of the resulting intermediate [107], the nature of the andgroup the [104,105,107,108], temperature applied, the stability all of which of the mayresulting have intermediate a signiﬁcant effect[107], onthe thenature course of the of heteroatom connected to the phosphorus atom [106], the solvent [106], the pH [109] and theheteroatom hydrolysis. connected to the phosphorus atom [106], the solvent [106], the pH [109] and the temperature applied, all of which may have a significant effect on the course of the the temperatureTwo equivalents applied, of NaOH all of which in water may were have used a significant in the hydrolysis effect on of the a series course of of ethyl the phosphinateshydrolysis. (58) carried out with stirring at 80 ◦C for 6–12 h. The sodium salt formed duringTwo the equivalents alkaline hydrolysis of NaOH was in converted water were to freeused acid in (the5)by hydrolysis treatment of with a series hydrochloric of ethyl acidphosphinates in the second (58) stepcarried (Scheme out with 29)[ stirring110]. at 80 °C for 6–12 h. The sodium salt formed during the alkaline hydrolysis was converted to free acid (5) by treatment with hydrochloric acid in the second step (Scheme 29) [110].

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Scheme 29. NaOH-catalyzed hydrolysis of a series of ethyl phosphinates (58). SchemeScheme 29.29. NaOH-catalyzedNaOH-catalyzed hydrolysis hydrolysis ofof aa seriesseries ofof ethylethyl phosphinatesphosphinates ((5858).).). The steric effects play a significant role [111]. The alkaline hydrolysis of the ethyl TheThe stericsteric effectseffects playplay aaa signiﬁcantsignificantsignificant rolerolerole [[1[111111].11].]. TheThe alkalinealkaline hydrolysishydrolysis ofof thethethe ethylethylethyl diethyl, diisopropyl and di-tert-butyl phosphinates (58) was studied (Scheme 30). It was diethyl,diethyl, diisopropyldiisopropyl andand di-di-terttert-butyl-butyl phosphinatesphosphinates ((5858)) waswas studiedstudiedstudied (Scheme(Scheme(Scheme 3030).30).). ItItIt waswaswas found that the increase in the steric hindrance decreased the reaction rate significantly foundfound thatthatthat the thethe increase increaseincrease in inin the thethe steric stericsteric hindrance hindrahindrancence decreased decreaseddecreased the reactionthethe reactionreaction rate signiﬁcantly raterate significantlysignificantly [111]. [111]. Relative rate constants of 260, 41 and 0.08 were reported for the alkaline hydrolysis Relative[111].[111]. RelativeRelative rate constants raterate constantsconstants of 260, ofof 41260,260, and 4141 0.08andand 0.080.08 were werewere reported reportedreported for theforfor thethe alkaline alkalinealkaline hydrolysis hydrolysishydrolysis of of the diethyl ester (at 70◦ °C), the diisopropyl ester (at 120◦ °C) and the di-tert-butyl ester theofof thethe diethyl diethyldiethyl ester esterester (at (at(at 70 7070C), °C),°C), the thethe diisopropyl diisopropyldiisopropyl ester esterester (at (at(at 120 120120 °C)C)°C) and andand the thethe di- di-di-tertterttert-butyl-butyl-butyl esteresterester (at 120 ◦°C). (at(at 120120 °C).°C).C).

Scheme 30. Base-catalyzed hydrolysis of a series of ethyl phosphinates (58). SchemeScheme 30.30. Base-catalyzedBase-catalyzed hydrolysishydrolysis ofof aa seriesseries ofof ethylethyl phosphinatesphosphinates ((5858).).). In the alkaline hydrolysis of sterically hindered phosphinates (59), ethyl di-tert-bu- In the alkaline alkaline hydrolysis hydrolysis of of ster stericallyically hindered hindered phosphinates phosphinates (59 (),59 ethyl), ethyl di-tert di--bu-tert- tylphosphinateInIn thethe alkalinealkaline hydrolyzed hydrolysishydrolysis 500 ofoftimes sterster slowericallyically hinderedhindered than ethyl phosphinatesphosphinates diisopropylphosphinate ((5959),), ethylethyl di-di- (Schemeterttert-bu--bu- tylphosphinatebutylphosphinate hydrolyzed hydrolyzed 500 times 500times slower slower than ethyl than diisopropylphosphinate ethyl diisopropylphosphinate (Scheme 31)tylphosphinatetylphosphinate [112]. The major hydrolyzedhydrolyzed factors influencing 500500 timestimes slowerslower the alkaline thanthan ethylethyl hydrolysis diisopropylphosphinatediisopropylphosphinate of the P-esters are the (Scheme(Scheme steric (Scheme31) [112].31 The) [ 112major]. The factors major influencing factors influencing the alkaline the hydrolysis alkaline of hydrolysis the P-esters of are the theP-esters steric hindrance31)31) [112].[112]. TheThe within majormajor the factorsfactors phosphinate influencinginfluencing and thethe alkalinestrengalkalineth hydrolysis hydrolysisof the acid of ofresulting thethe PP-esters-esters from areare the thethe hydrol- stericsteric hindranceare the steric within hindrance the phosphinate within the and phosphinate the strength and of the the acid strength resulting of the from acid the resulting hydrol- hindrancehindrance withinwithin thethe phosphinatephosphinate andand thethe strengstrengthth ofof thethe acidacid resultingresulting fromfrom thethe hydrol-hydrolysis.from the hydrolysis. ysis.ysis.

Scheme 31. Base-catalyzed hydrolysis of sterically hindered phosphinates (59).). SchemeScheme 31.31. Base-catalyzedBase-catalyzed hydrolysishydrolysis ofof stericallysterically hinderedhindered phosphinatesphosphinates ((5959).). During the the hydrolysis hydrolysis of of 1- 1-alkoxyphospholenealkoxyphospholene oxides, oxides, it itwas was found found that, that, under under alka- al- DuringDuring thethe hydrolysishydrolysis ofof 1-1-alkoxyphospholenealkoxyphospholene oxides,oxides, itit waswas foundfound that,that, underunder alka-alka- linekaline conditions, conditions, the the1-alkoxy-3-phospholene 1-alkoxy-3-phospholene oxide oxide hydrolyzed hydrolyzed 40 times 40 timesfaster fasterthan the than 1- lineline conditions,conditions, thethe 1-alkoxy-3-phospholene1-alkoxy-3-phospholene oxoxideide hydrolyzedhydrolyzed 4040 timestimes fasterfaster thanthan thethe 1-1- alkoxy-2-phospholenethe 1-alkoxy-2-phospholene oxide [104]. oxide In [104 anot].her In another paper, a paper, series aof seriesmethyl of esters methyl (4) esters(Scheme (4) alkoxy-2-phospholenealkoxy-2-phospholene oxideoxide [104].[104]. InIn anotanotherher paper,paper, aa seriesseries ofof methylmethyl estersesters ((44)) (Scheme(Scheme (Scheme32) and other 32) and cyclic other phosphinates cyclic phosphinates were investigated were investigated in order into orderclarify to the clarify effect the of effectalkyl 32)32) andand otherother cycliccyclic phosphinatesphosphinates werewere investigatedinvestigated inin orderorder toto clarifyclarify thethe effecteffect ofof alkylalkyl groupsof alkyl and groups rings and [113]. rings In [this113]. case, In this the case,reaction the reactionconditions conditions and the yields and the were yields not were pro- groupsgroups andand ringsrings [113].[113]. InIn thisthis case,case, thethe reactionreaction conditionsconditions andand thethe yieldsyields werewere notnot pro-provided.not provided. vided.vided.

Scheme 32. Base-catalyzed hydrolysis of a series of acyclic methyl phosphinates (4).

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SchemeScheme 32. 32. Base-catalyzed Base-catalyzed hydrolysis hydrolysis of of a aseries series of of acyclic acyclic methyl methyl phosphinates phosphinates (4 ().4 ). Scheme 32. Base-catalyzedScheme 32. Base-catalyzed hydrolysis of hydrolysis a series of ofacyclic a series methyl of acyclic phosphinates methyl phosphinates (4). (4). Scheme 32. Base-catalyzed hydrolysis of a series of acyclic methyl phosphinates (4). The order of reactivity for the open chain derivatives was the following [113]: TheThe order order of ofThe reactivity reactivity order of for forreactivity the thethe open openopen for chain chainchain the derivativesopen derivativesderivatives chain derivativeswas waswas the thethe following followingfollowing was the [113]: [[113]:following113]: [113]: The order of reactivity for theMe openMe > >Ph chainPh > >Bn Bnderivatives > >Et Et > >n BunBu was the following [113]: Me > Ph > BnMe > Et> Ph > n >Bu Bn > Et > nBu MeMe > > Ph Ph > > BnBn >> EtEt >> nBu

In the case of cyclic derivatives, the following order of reactivity was found [113]: InIn the the case case ofIn of cyclic the cyclic case derivatives, derivatives, of cyclic derivatives, the the following following the order orderfollowing of of reactivity reactivity order of was wasreactivity found found [113]:was [113]: found [113]: InIn the the case case of of cyclic cyclic derivatives, derivatives, the the following following order order of of reactivity reactivity was was found found [113]: [113]:

The alkaline hydrolysis of other cyclic and open-chain phosphinates was also studied TheThe alkaline alkalineThe hydrolysis hydrolysis alkaline of hydrolysis of ot otherher cyclic cyclic of otand andher open-chain open-chaincyclic and phosphinatesopen-chain phosphinates phosphinates was was also also studied studied was also studied [114]The andThe alkaline the alkaline rate hydrolysis constants hydrolysis ofwere ofother other determined. cyclic cyclic and and open-chain In open-chain the case phosphinates of phosphinatesless-soluble was phosphinates, was also also studied stud- [114][114] and and the the[114] rate rate and constants constants the rate were wereconstants determined. determined. were determined. In In the the case case Inof of theless-soluble less-soluble case of less-solublephosphinates, phosphinates, phosphinates, alcohol–water[114]ied [114and] andthe ratemixtures the rateconstants constants were wereused. were determined.The determined. hydrolysis In Intheof thefive-membered case case of ofless-soluble less-soluble cyclic phosphinates,phosphinates phosphinates, alcohol–wateralcohol–wateralcohol–water mixtures mixtures were were mixtures used. used. Thewere The hydrol hydrolused.ysis Theysis ofhydrol of five-membered five-memberedysis of five-membered cyclic cyclic phosphinates phosphinates cyclic phosphinates wasalcohol–wateralcohol–water faster than mixtures that mixtures of the were were open-chain used. used. The The and hydrol hydrolysis six-memberedysis of of five-membered ﬁve-membered cyclic phosphinates cyclic cyclic phosphinates phosphinates (Table 5). waswas faster faster than wasthan thatfaster that of of thanthe the open-chain thatopen-chain of the open-chainand and six-membered six-membered and six-membered cyclic cyclic phosphinates phosphinates cyclic phosphinates (Table (Table 5). 5). (Table 5). waswas faster faster than than that that of of the the open-chain open-chain and and six-membered six-membered cyclic cyclic phosphinates phosphinates (Table (Table 55).). TableTable 5. 5. The The alkaline alkaline hydrolysis hydrolysis of of various various cy cyclicclic and and open-chain open-chain phosphinates. phosphinates. Table 5. The Tablealkaline 5. hydrolysisThe alkaline of hydrolysis various cy clicof various and open-chain cyclic and phosphinates. open-chain phosphinates. TableTable 5. 5. TheThe alkaline alkaline hydrolysis hydrolysis of of various various cy cyclicclic and and open-chain open-chain phosphinates. phosphinates. −1−1 −1−1 4 4 RateRate Constant, Constant, 1 1mole mole−1 s −s1 × ×10 104 −1 −1 4 StartingStarting Phosphinate Phosphinate Solvent Solvent Rate Constant,Rate 1 Constant,mole−1 s−1 1× mole10 4 s × 10 Starting PhosphinateStarting Phosphinate Solvent Solvent50 Rate50Rate °C °C Constant, Constant,6060 1 1°C mole °Cmole −1s s−1 ×70 701010 °C 4°C StartingStarting Phosphinate Solvent 50 °C 50 °C60 °C 60 °C70 °C 70 °C 50 50°C◦ C60 60 °C◦C 7070◦ °CC 50% alcohol–water 1.18 2.24 4.22 50%50% alcohol–water alcohol–water50% alcohol–water 1.18 1.18 1.18 2.24 2.24 2.24 4.22 4.22 4.22 50%50% alcohol–water 1.18 1.18 2.24 2.24 4.22 4.22

80%80% alcohol–water alcohol–water 0.300 0.300 0.568 0.568 1.08 1.08 80%80% alcohol–water 80% alcohol–water 0.300 0.300 0.300 0.568 0.568 0.568 1.08 1.08 1.08 80% alcohol–water 0.300 0.568 1.08

50%50% alcohol–water 0.730 0.730 1.39 1.39 2.63 2.63 50%50% alcohol–water alcohol–water50% alcohol–water 0.730 0.730 0.730 1.39 1.39 1.39 2.63 2.63 2.63 50% alcohol–water 0.730 1.39 2.63

The effect of various heteroaromatic substituents was also studied in the hydrolyses TheThe effect effect of ofThe various various effect heteroaromatic of heteroaromatic various heteroaromatic substi substituentssubstituentstuents substi was was alsotuents also studied studied was also in in the studied the hydrolyses hydrolyseshydrolyses in the hydrolyses carriedThe out effect in 50% of various aqueous heteroaromatic dioxane: the hydrolysissubstituents of was di(2-furyl)-, also studied di(2-thienyl)- in the hydrolyses and di- carriedcarried out out out carriedin in in 50% 50% 50% aqueousout aqueous aqueous in 50% dioxane: dioxane: dioxane:aqueous the the dioxane: thehydrolysis hydrolysis hydrolysis the ofhydrolysis of di(2-furyl)-, ofdi(2-furyl)-, di(2-furyl)-, of di(2-furyl)-,di(2-thienyl)- di(2-thienyl)- di(2-thienyl)- di(2-thienyl)- and and anddi- di- and di- phenylphosphiniccarried out in 50% acidaqueous ethyl dioxane: esters performed the hydrolysis using oneof di(2-furyl)-, equivalent di(2-thienyl)-of sodium hydroxide and di- phenylphosphinicdiphenylphosphinicphenylphosphinicphenylphosphinic acid acid acid ethyl ethyl ethyl esters estersacid esters ethylperformed performed performed esters usingperformed using using one one one equivalent equivalentusing equivalent one of equivalent of of sodium sodium sodium hydroxide ofhydroxide sodium hydroxide forphenylphosphinic 72–120 h was compared acid ethyl (Figure esters performed 5) [115]. It usingwas found one equivalent that the hydrolysis of sodium of hydroxide the furyl forfor 72–120 72–120 h for hwas was 72–120 compared compared h was (Figure compared (Figure 5)5 5))[ [115]. [115].(Figure115]. It It was 5) waswas [115]. found foundfound It thatwas thatthat thefound thethe hydrolysis hydrolysishydrolysis that the ofhydrolysis ofof the thethe furyl furylfuryl of the furyl derivativeforderivative 72–120 wash was was the the compared fastest, fastest, while while(Figure that that 5) of of[115]. the the phenyl phenylIt was speciesfound species thatwas was thethe the hydrolysisslowest. slowest. of the furyl derivativederivative was derivativewas the the fastest, fastest, was whilethe while fastest, that that of whileof the the phenyl thatphenyl of speciesthe species phenyl was was speciesthe the slowest. slowest. was the slowest. derivative was the fastest, while that of the phenyl species was the slowest.

FigureFigure 5. 5. The The effect effect of of various various heteroaromatic heteroaromatic substituents substituents in inin alkaline alkalinealkaline hydrolysis. hydrolysis.hydrolysis. Figure 5. TheFigure effect of5. variousThe effect heteroaromatic of various heteroaromatic substituents insubstituents alkaline hydrolysis. in alkaline hydrolysis. Figure 5. The effect of various heteroaromatic substituents in alkaline hydrolysis. Bergesen investigated the difference between the alkaline hydrolysis of the cis and trans BergesenBergesen investigated investigated the the difference difference be betweentween the the alkaline alkaline hydrolysis hydrolysis of of the the cis cis and and isomersBergesen of a four-membered investigatedBergesen investigated the cyclic difference phosphinate the be differencetween (60 )the in be 50%alkalinetween ethanol–water the hydrolysis alkaline(Scheme ofhydrolysis the cis 33 )and[ 39of ].the cis and transtrans Bergesenisomers isomers of investigatedof a afour-membered four-membered the difference cyclic cyclic phosphinate phosphinatebetween the ( 60 (alkaline60) )in in 50% 50% hydrolysis ethanol–water ethanol–water of the (Scheme (Schemecis and transThe isomers resultstrans showedof a isomers four-membered that of the a four-memberedcis isomer cyclic phosphinate hydrolyzed cyclic phosphinate ca.(60) sevenin 50% times (ethanol–water60) in faster. 50% ethanol–water This (Scheme may be (Scheme 33)trans33) [39]. [39].isomers The The resultsof results a four-membered showed showed that that thecyclic the cis cis phosphinateisomer isomer hydrolyzed hydrolyzed (60) in 50%ca. ca. seven ethanol–waterseven times times faster. faster. (Scheme This This 33)explained [39]. The by33) results the [39]. fact Theshowed that, results in that the showed case the ofcis the thatisomertrans the hydrolyzed isomer,cis isomer the threehydrolyzedca. seven methyl times ca. groups seven faster. block times This the faster. This may33)may [39]. be be explained Theexplained results by by showedthe the fact fact that,that that, inthe in the thecis case isomercase of of the thehydrolyzed trans trans isomer, isomer, ca. theseven the three three times methyl methyl faster. groups groups This Molecules 2021, 26, x FOR PEER REVIEWmayaccess be ofexplained themay hydroxy be by explained the ion, fact as that, comparedby the in factthe to casethat, the of in case the the when trans case onlyisomer,of the two trans the methyl threeisomer, groups methyl the three are groups17 in methylof the 35 groups blockmayblock be the the explained access access of of bythe the the hydroxy hydroxy fact that, ion, ion, in as asthe compared compared case of theto to the trans the case case isomer, when when theonly only three two two methyl methyl groups groups blockneighborhood, the accessblock of as the the in access thehydroxycis ofisomer. the ion, hydroxy as compared ion, as to compared the case when to the only case two when methyl only twogroups methyl groups areblock in thethe accessneighborhood, of the hydroxy as in the ion, cis as isomer. compared to the case when only two methyl groups areare in in the the neighborhood, neighborhood,are in the neighborhood, as as in in the the cis cis asisomer. isomer. in the cis isomer. are in the neighborhood, as in the cis isomer.

Scheme 33. Alkaline hydrolysis of thethe isomers of a four-membered cycliccyclic phosphinatephosphinate ((6060).).

The alkaline hydrolysis of different alkyl diethylphosphinates (59) was also investigated (Scheme 34) [38]. The reactivity of the alkoxy groups was influenced by the steric bulk of the alkyl group. The value of the rate constants decreased with the increase of the steric hindrance. However, the exact conditions and outcomes were not reported.

Scheme 34. Alkaline hydrolysis of diethyl phosphinates (59) in a DMSO-water system.

It was confirmed by another group that the base-catalyzed hydrolysis became less efficient with the increasing steric requirement of the alkyl group of the alkoxy moiety [104]. Furthermore, 1-Hydroxy-3,4-diphenylphosphole-1-oxide (63) was prepared from the corresponding phenoxyphosphole oxide (62) by alkaline hydrolysis (Scheme 35) [105]. Then, the corresponding phosphinic acid (61) was liberated with HCl.

Scheme 35. NaOH-catalyzed hydrolysis of 1-phenoxy-3,4-diphenylphosphol oxide (62).

Studying the hydrolysis of different esters, Clarke and co-workers concluded that the smaller the electron-releasing effect of the substituents was, the greater the rate constant became (Figure 6) [105].

. Figure 6. The reactivity order of different cyclic phosphinates in alkaline hydrolysis.

The NaOH-catalyzed hydrolysis of substituted aryl diphenylphosphinates (64) was also investigated (Scheme 36) [106]. It was found that the value of the rate constant decreased with the decrease of the electron-withdrawing ability of the substituent Y in the departing aryl ring. All of the reactions were carried out under pseudo–first-order kinetic conditions, but the exact circumstances were not reported.

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Molecules 2021, 26, x FOR PEER REVIEW 17 of 35

Molecules 2021, 26, 2840 Scheme 33. Alkaline hydrolysis of the isomers of a four-membered cyclic phosphinate (60). 16 of 33 Scheme 33. Alkaline hydrolysis of the isomers of a four-membered cyclic phosphinate (60). Scheme 33. Alkaline hydrolysis of the isomers of a four-membered cyclic phosphinate (60). The alkaline hydrolysis of different alkyl diethylphosphinates (59) was also investigated (Scheme 34) [38]. The reactivity of the alkoxy groups was influenced by the steric gatedThe (Scheme alkaline 34) hydrolysis [38]. The reactivityof differ differentent of alkylthe alkoxy diethylphosphinates groups was influenced ( 59)) was was byalso the investi- steric bulk of the alkyl group. The value of the rate constants decreased with the increase of the gatedbulk of (Scheme the alkyl 34)34 group.)[ [38].38]. The vareactivity lue of the of rate the alkoxyconstants groups decrea wassed inﬂuencedinfluenced with the increase by the stericofsteric the steric hindrance. However, the exact conditions and outcomes were not reported. bulksteric of hindrance. the alkyl group.However, The the va valuelue exact of the conditions rate constants and outcomes decrea decreasedsed were with not the reported. increase of the steric hindrance. However, the exact conditions and outcomes werewere notnot reported.reported.

Scheme 34. Alkaline hydrolysis of diethyl phosphinates (59) in a DMSO-water system. Scheme 34. Alkaline hydrolysis of diethyl phosphinates (59) in a DMSO-water system. Scheme 34. Alkaline hydrolysis of diethyl phosphinates (59) in a DMSO-water system.system. It was confirmed by another group that the base-catalyzed hydrolysis became less efficient with the increasing steric requirement of the alkyl group of the alkoxy moiety efficientIt was with conﬁrmedconfirmed the increasing by anotheranother steric groupgrouprequirem thatthatent thethe of base-catalyzedbase-catalyzed the alkyl group hydrolysishydrolysis of the alkoxy becamebecame moiety lessless [104]. efficientefﬁcient[104]. withwith thethe increasing increasing steric steric requirement requirement of theof the alkyl alkyl group group of the of alkoxy the alkoxy moiety moiety [104]. Furthermore, 1-Hydroxy-3,4-diphenylphosphole-1-oxide (63) was prepared from the [104].Furthermore, 1-Hydroxy-3,4-diphenylphosphole-1-oxide1-Hydroxy-3,4-diphenylphosphole-1-oxide ((6363)) waswas preparedprepared fromfrom thethe corresponding phenoxyphosphole oxide (62) by alkaline hydrolysis (Scheme 35) [105]. correspondingFurthermore, phenoxyphosphole 1-Hydroxy-3,4-diphenylphosphole-1-oxide oxide ( 62)) by alkaline hydrolysis (63) was (Scheme prepared 35)35 from)[ [105].105 the]. Then, the corresponding phosphinic acid (61) was liberated with HCl. Then,corresponding the corresponding phenoxyphosphole phosphinicphosphinic oxide acidacid (((616162))) waswasby alkaline liberatedliberated hydrolysis withwith HCl.HCl. (Scheme 35) [105]. Then, the corresponding phosphinic acid (61) was liberated with HCl.

Scheme 35. NaOH-catalyzed hydrolysis of 1-phenoxy-3,4-diphenylphosphol oxide (62). Scheme 35. NaOH-catalyzed hydrolysis of 1-phenoxy-3,4-diphenylphosphol1-phenoxy-3,4-diphenylphosphol oxideoxide ((6262).). Scheme 35. NaOH-catalyzed hydrolysis of 1-phenoxy-3,4-diphenylphosphol oxide (62). Studying the hydrolysis of different esters, Clarke and co-workers concludedconcluded thatthat thethe smaller the electron-releasing effect of the substituentssubstituents was, the greater thethe raterate constantconstant smallerStudying the electron-releasing the hydrolysis of effect different of the esters, substituents Clarke and was, co-workers the greater concluded the rate constant that the became (Figure6 6))[ [105].105]. smallerbecame the(Figure electron-releasing 6) [105]. effect of the substituents was, the greater the rate constant became (Figure 6) [105].

. Figure 6. The reactivity order of differentdifferent cyclic phosphinatesphosphinates inin alkalinealkaline hydrolysis.hydrolysis. Figure 6. The reactivity order of different cyclic phosphinates in alkaline hydrolysis.. FigureThe 6. The NaOH-catalyzed reactivity order hydrolysisof different cyclic of substituted phosphinates aryl in diphenylphosphinates alkaline hydrolysis. (64) was The NaOH-catalyzed hydrolysis of substituted aryl diphenylphosphinates (64) was also investigated (Scheme (Scheme 36)36 )[[106].106]. It Itwas was found found that that the the value value of the of therate rate constant constant de- also Theinvestigated NaOH-catalyzed (Scheme hydrolysis36) [106]. It of was substituted found that aryl the diphenylphosphinates value of the rate constant (64) was de- decreasedcreased with with the the decrease decrease of of the the electron-wit electron-withdrawinghdrawing ability ability of of the the substituent substituent Y in the Molecules 2021, 26, x FOR PEER REVIEWalsocreased investigated with the decrease(Scheme of36) the [106]. electron-wit It was fohdrawingund that theability value of ofthe the substituent rate constant Y 18in of de-the 35 departing aryl ring. All of the reactions were carried out under pseudo–ﬁrst-orderpseudo–first-order kinetic creasedconditions,departing with aryl but the ring. the decrease exact All of circumstances theof the reactions electron-wit were notcarriedhdrawing reported. out ability under ofpseudo–first-order the substituent Y kinetic in the conditions, but the exact circumstances were not reported. departingconditions, aryl but ring. the exact All of circumstances the reactions werewere carriednot reported. out under pseudo–first-order kinetic conditions, but the exact circumstances were not reported.

Scheme 36. NaOH-calatyzed hydrolysis of variousvarious aryl diphenylphosphinates ((6464).).

Hydrolyses of various aryl diphenylphosphinates (64) carried out using OH– and imidazole catalysis were compared (Scheme 37) [116]. In addition to the substituent dependence, it was found that the imidazole-promoted hydrolyses were significantly faster than the OH–-catalyzed examples. This paper was merely a kinetic study, and the exact conditions were not reported.

Scheme 37. OH– ion- and imidazole-calatyzed hydrolysis of various aryl diphenylphosphinates (64).

The effect of alkyl groups was also studied in the case of diphenylphosphinothioates. It was found that the electron-withdrawing effect accelerates the process, whilst the electron-releasing effect greatly slows it down [117]. It was also found that thioesters (>P(O)SR) are much more reactive than the oxo analogues. The reason is that the RS substituent is a better leaving group. In addition, the R group has a greater influence on the hydrolyzing ability of OR than it does on that of SR [106,118]. Comparing the reactivity of the P=O and P=S derivatives, it can be said that in the case of alkaline hydrolysis, the oxo derivatives are more reactive. [106,109]. The effect of solvents and solvent mixtures was also studied. It was found that the hydrolysis was slightly faster in solvent mixtures [106]. Possible solvent mixtures may be 60% dimethoxyethane in water [104,114], 60% dimethyl ether in water [106], 20% acetonitrile in water [119], and 60% acetone in water [117], but there are other options as well, e.g., hydrolysis in dioxane–water [117] or in methanol–water [117].

3.2. Alkaline and Basic Hydrolysis of Phosphonates The alkaline hydrolysis of a series of diethyl alkylphosphonates (65) was investigated in DMSO/H2O. Based on the results, an order of reactivity was established on the basis of the nature of the various alkyl chains (Scheme 38) [38]. Higher reactivity was observed for the esters with an n-alkyl substituent, while the rate of the hydrolysis decreased with increasing steric hindrance.

Molecules 2021, 26, x FOR PEER REVIEW 18 of 35

Molecules 2021, 26, 2840 17 of 33 Scheme 36. NaOH-calatyzed hydrolysis of various aryl diphenylphosphinates (64).

Hydrolyses of various various aryl aryl diphenylphosphinates diphenylphosphinates (64 (64) carried) carried out out using using OH OH– and– and im- imidazoleidazole catalysis catalysis were were compared compared (Scheme (Scheme 37) [ 116].37)[ In116 addition]. In addition to the substituent to the substituent depend- dependence,ence, it was found it was that found the that imidazole-promoted the imidazole-promoted hydrolyses hydrolyses were weresignificantly signiﬁcantly faster faster than thanthe OH the–-catalyzed OH–-catalyzed examples. examples. This paper This paperwas mere wasly merely a kinetic a kinetic study, study,and the and exact the condi- exact conditionstions were werenot reported. not reported.

Scheme 37.37. OH–– ion- and imidazole-calatyzedimidazole-calatyzed hydrolysishydrolysis of of various various aryl aryl diphenylphosphinates diphenylphosphinates (64 ). (64). The effect of alkyl groups was also studied in the case of diphenylphosphinothioates. It was foundThe effect that of the alkyl electron-withdrawing groups was also studied effect accelerates in the case theof diphenylphosphinothioates. process, whilst the electron- releasingIt was found effect that greatly the electron-withdrawing slows it down [117]. effect accelerates the process, whilst the electron-releasingIt was also effect found greatl thaty slows thioesters it down (>P(O)SR) [117]. are much more reactive than the oxo analogues.It was Thealso reasonfound isthat that thioesters the RS substituent (>P(O)SR) isare a bettermuch leavingmore reactive group. than In addition, the oxo thean- Ralogues. group hasThe areason greater is inﬂuencethat the RS on substituen the hydrolyzingt is a better ability leaving of OR group. than itIn doesaddition, on that the of R SRgroup [106 has,118 a]. greater Comparing influence the reactivity on the hydrolyzing of the P=O ability and P=S of derivatives,OR than it does it can on be that said of that SR in[106,118]. the case Comparing of alkaline hydrolysis,the reactivity the of oxo the derivatives P=O and P=S are derivatives, more reactive. it can [106 be,109 said]. that in the caseThe of effect alkaline of solvents hydrolysis, and the solvent oxo derivatives mixtures wasare more also reactive. studied. [106,109]. It was found that the hydrolysisThe effect wasof solvents slightly and faster solvent in solvent mixtures mixtures was also [106 studied.]. Possible It was solvent found mixtures that the may be 60% dimethoxyethane in water [104,114], 60% dimethyl ether in water [106], 20% hydrolysis was slightly faster in solvent mixtures [106]. Possible solvent mixtures may be acetonitrile in water [119], and 60% acetone in water [117], but there are other options as 60% dimethoxyethane in water [104,114], 60% dimethyl ether in water [106], 20% acetoni- well, e.g., hydrolysis in dioxane–water [117] or in methanol–water [117]. trile in water [119], and 60% acetone in water [117], but there are other options as well, 3.2.e.g., Alkalinehydrolysis and in Basic dioxane–water Hydrolysis of [117] Phosphonates or in methanol–water [117]. The alkaline hydrolysis of a series of diethyl alkylphosphonates (65) was investigated 3.2. Alkaline and Basic Hydrolysis of Phosphonates in DMSO/H2O. Based on the results, an order of reactivity was established on the basis of theThe nature alkaline of the hydrolysis various alkyl of a seri chainses of (Scheme diethyl alkylphosphonates38)[38]. Higher reactivity (65) was was investigated observed Molecules 2021, 26, x FOR PEER REVIEWin DMSO/H 2O. Based on the results, an order of reactivity was established on the basis19 of of35 for the esters with an n-alkyl substituent, while the rate of the hydrolysis decreased with increasingthe nature stericof the hindrance.various alkyl chains (Scheme 38) [38]. Higher reactivity was observed for the esters with an n-alkyl substituent, while the rate of the hydrolysis decreased with in- creasingO steric hindrance. NaOH O R P OEt R P OH DMSO/H O OEt 2 OH 65 66 n i n i s R=Me,Et, Pr, Pr, Bu, Bu, Bu, Hex, Oct, Dodecyl Scheme 38. Alkaline hydrolysis of diethyldiethyl alkylphosphonates ((6565)) inin aqueousaqueous DMSODMSO solution.solution.

The stericsteric effectseffects had had a greatera greater inﬂuence influence on on the the hydrolysis hydrolysis of phosphonates of phosphonates compared com- topared that to of that carboxylic of carboxylic esters. esters. In addition, In addition it, was it was found found that that the the hydrolysis hydrolysis of of six- six- andand seven-membered cycliccyclic phosphonates is faster than that of the open-chain analogues [38]. [38]. It waswas observedobserved that thethe raterate ofof thethe hydrolysishydrolysis waswas greatlygreatly inﬂuencedinfluenced byby thethe naturenature of the leaving groupgroup andand thethe substituentssubstituents onon thethe phosphorusphosphorus atom.atom. AksnesAksnes etet al.al. studiedstudied the alkalinealkaline hydrolysis hydrolysis of variousof various diethyl diethyl alkyl-, chloromethyl-alkyl-, chloromethyl- and dichloromethylphos- and dichloro- phonatesmethylphosphonates (65) in an acetone–water (65) in an acetone–water solvent-mixture solvent-mixture (Scheme 39)[ (Scheme120]. The 39) presence [120]. The of thepresence chloromethyl of the chloromethyl or dichloromethyl or dichlorometh substituentsyl substituents increased the increased reaction the rate. reaction Compared rate. Compared to the hydrolysis of carboxylic esters, the hydrolysis of phosphonates is less sensitive to electronic effects.

Scheme 39. Hydrolysis of diethyl phosphonates (65) in aqueous acetone.

As an interesting example, a diphenyl adenosilvinylphosphonate (67) was hydrolyzed in the presence of ammonium fluoride (Scheme 40) [121].

Scheme 40. NH4F-catalyzed hydrolysis of an adenosilvinylphosphonate derivative (67).

Other vinylphosphonic esters (69) were hydrolyzed under similar conditions (Scheme 41) [121].

Scheme 41. NH4F-catalyzed hydrolysis of a series of diphenyl vinylphosphonates (69).

Molecules 2021, 26, x FOR PEER REVIEW 19 of 35 Molecules Molecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW 1919 ofof 3535

O O OO NaOH OO R P OEt NaOHNaOH R P OH R P OEt R P OH R P OEt DMSO/H2O R P OH OEt DMSO/HDMSO/H2OO OH OEtOEt 2 OHOH 65 66 65 66 65 n i n i s 66 R=Me,Et,nPr, iPr, nBu, iBu,sBu, Hex, Oct, Dodecyl R=Me,Et,n Pr, i Pr, n Bu, i Bu,s Bu, Hex, Oct, Dodecyl R=Me,Et, Pr, Pr, Bu, Bu, Bu, Hex, Oct, Dodecyl Scheme 38. Alkaline hydrolysis of diethyl alkylphosphonates (65) in aqueous DMSO solution. SchemeScheme 38.38. AlkalineAlkaline hydrolysishydrolysis ofof didiethylethyl alkylphosphonatesalkylphosphonates ((6565)) inin aqueousaqueous DMSODMSO solution.solution. The steric effects had a greater influence on the hydrolysis of phosphonates com- The steric effects had a greater influence on the hydrolysis of phosphonates com- paredThe to thatsteric of effectscarboxylic had esters.a greater In addition influence, it onwas the found hydrolysis that the of hydrolysis phosphonates of six- com- and pared to that of carboxylic esters. In addition, it was found that the hydrolysis of six- and paredseven-membered to that of carboxylic cyclic phosphonates esters. In addition is faster, it than was that found of thethat open-chain the hydrolysis analogues of six- [38].and seven-membered cyclic phosphonates is faster than that of the open-chain analogues [38]. seven-memberedIt was observed cyclic that phosphonates the rate of the is fasterhydrol thanysis thatwas ofgreatly the open-chain influenced analogues by the nature [38]. It was observed that the rate of the hydrolysis was greatly influenced by the nature of theIt leavingwas observed group andthat thethe substituentsrate of the hydrol on theysis phosphorus was greatly atom. influenced Aksnes byet al.the studied nature of the leaving group and the substituents on the phosphorus atom. Aksnes et al. studied ofthe the alkaline leaving grouphydrolysis and theof substituents various diethyl on the phosphorusalkyl-, chloromethyl- atom. Aksnes and et al.dichloro- studied Molecules 2021, 26, 2840 the alkaline hydrolysis of various diethyl alkyl-, chloromethyl- and dichloro-18 of 33 themethylphosphonates alkaline hydrolysis (65) inof anvarious acetone–water diethyl solvent-mixturealkyl-, chloromethyl- (Scheme and39) [120].dichloro- The methylphosphonates (65) in an acetone–water solvent-mixture (Scheme 39) [120]. The methylphosphonatespresence of the chloromethyl (65) in anor dichloromethacetone–wateryl solvent-mixturesubstituents increased (Scheme the 39) reaction [120]. rate.The presence of the chloromethyl or dichloromethyl substituents increased the reaction rate. presenceCompared of tothe the chloromethyl hydrolysis ofor carboxylicdichlorometh esteylrs, substituents the hydrolysis increased of phosphonates the reaction is rate. less Compared to the hydrolysis of carboxylic esters, the hydrolysis of phosphonates is less Comparedtosensitive the hydrolysis to toelectronic the ofhydrolysis carboxylic effects. of esters,carboxylic the hydrolysis esters, the ofhydrolysis phosphonates of phosphonates is less sensitive is less to sensitive to electronic effects. sensitiveelectronic to effects. electronic effects.

Scheme 39. Hydrolysis of diethyl phosphonates (65) in aqueous acetone. SchemeScheme 39. 39. HydrolysisHydrolysis of of diet diethyldiethylhyl phosphonates phosphonates ((6565)) inin aqueousaqueous acetone.acetone. As an interesting example, a diphenyl adenosilvinylphosphonate (67) was hydro- As anan interestinginteresting example, example, a diphenyla diphenyl adenosilvinylphosphonate adenosilvinylphosphonate (67) ( was67) hydrolyzedwas hydro- lyzedAs in anthe interesting presence of example, ammonium a diph fluorideenyl adenosilvinylphosphonate(Scheme 40) [121]. (67) was hydro- lyzedinlyzed the in presencein thethe presencepresence of ammonium ofof ammoniumammonium ﬂuoride fluoridefluoride (Scheme (Scheme(Scheme 40)[121 40)40)]. [121].[121].

Scheme 40. NH4F-catalyzed hydrolysis of an adenosilvinylphosphonate derivative (67). Scheme 40.40. NH4F-catalyzed hydrolysis of an adenosilvinylphosphonate derivative (67). Scheme 40. NH4F-catalyzedF-catalyzed hydrolysis hydrolysis of of an an aden adenosilvinylphosphonateosilvinylphosphonate derivative ( 67).). Other vinylphosphonicvinylphosphonic esters esters ( 69)) werewere hydrolyzedhydrolyzed underunder similarsimilar conditionsconditions OtherOther vinylphosphonicvinylphosphonic estersesters ((6969)) werewere hydrolyzedhydrolyzed underunder similarsimilar conditionsconditions (Scheme 4141))[ [121].121]. (Scheme(Scheme 41)41) [121].[121].

Molecules 2021, 26, x FOR PEER REVIEW 20 of 35

Scheme 41. NH4F-catalyzedF-catalyzed hydrolysis hydrolysis of a series of diphenyl vinylphosphonates ( 69). Scheme 41. NH4F-catalyzed hydrolysis of a series of diphenyl vinylphosphonates (69). Scheme 41. NH4F-catalyzed hydrolysis of a series of diphenyl vinylphosphonates (69). It was noted that, in thethe casecase ofof benzylbenzyl esters,esters, thethe correspondingcorresponding acidsacids maymay alsoalso bebe obtained by catalytic hydrogenation. The enzyme-catalyzed hydrolysis of diphenyl alkylphosphonates ( (7171)) was was also also re- re-

ported [[121,122].121,122]. AsAs a a matter matter of of fact, fact, the the hydrolysis hydrolysis of the of ﬁrstthe esterfirst functionester function was performed was per- byformed applying by applying base catalysis, base catalysis, while a phosphodiesterase while a phosphodiesterase enzyme was enzyme used in was the secondused in step the (Schemesecond step 42). (Scheme 42).

Scheme 42. Semi-enzymatic hydrolysis of diphenyl alkylphosphonates (71).).

The above above phenomenon phenomenon was was investigated investigated by by several several groups. groups. Hudson Hudson et al. et also al. stud- also P studiedied the effect the effect of the of P the-substituents-substituents on the on reactivity the reactivity [92]. [ 92 ]. In the acidic hydrolysis of dialkyl methylphosphonates, the order of reactivity was the following [92]: iPr > Me > Et ~ neopentyl

In contrast, applying base-catalyzed hydrolysis, the order of reactivity was the following [92]: Me > Et > iPr > neopentyl

In the case of diaryl esters, the rate constants were significantly higher. The rate is dependent on the electronic effects: electron-donating substituents slow down the hydrolysis [92]. This was also observed for cyclic phosphonates [123]. Ring cleavage also takes place during their alkaline hydrolysis [109]. The alkaline hydrolysis of phenyl methylphosphonate and p-nitrophenyl methylphosphonate (74) with the application of NaOH was also studied (Scheme 43) [124]. In this case, the nucleophilic attack of the hydroxide ion occurs on the phosphorus atom of the P=O function. The rate of the reaction increased with the increase of the hydroxide ion concentration.

Scheme 43. Alkaline hydrolysis of aryl methylphosphonates 66 using NaOH.

Dimethyl 4-toluenesulfonyloxymethylphosphonate (75) was treated with 60% pyridine-H2O at room temperature to give the monomethyl derivative at an 82% yield (Scheme 44) [125]. The product was a good phosphorylating reagent to protect nucleosides.

Molecules 2021, 26, x FOR PEER REVIEW 20 of 35

It was noted that, in the case of benzyl esters, the corresponding acids may also be obtained by catalytic hydrogenation. The enzyme-catalyzed hydrolysis of diphenyl alkylphosphonates (71) was also reported [121,122]. As a matter of fact, the hydrolysis of the first ester function was performed by applying base catalysis, while a phosphodiesterase enzyme was used in the second step (Scheme 42).

Scheme 42. Semi-enzymatic hydrolysis of diphenyl alkylphosphonates (71).

Molecules 2021, 26, 2840 The above phenomenon was investigated by several groups. Hudson et al. also19 stud- of 33 ied the effect of the P-substituents on the reactivity [92]. In the acidic hydrolysis of dialkyl methylphosphonates, the order of reactivity was the following [92]: In the acidic hydrolysis of dialkyl methylphosphonates, the order of reactivity was iPr > Me > Et ~ neopentyl the following [92]: iPr > Me > Et ~ neopentyl In contrast, applying base-catalyzed hydrolysis, the order of reactivity was the fol- lowingIn [92]: contrast, applying base-catalyzed hydrolysis, the order of reactivity was the following [92]: Me > Et > iPr > neopentyl Me > Et > iPr > neopentyl In the case of diaryl esters, the rate constants were significantly higher. The rate is In the case of diaryl esters, the rate constants were signiﬁcantly higher. The rate isdependent dependent on onthe theelectronic electronic effects: effects: electron electron-donating-donating substituents substituents slow down slow the down hydrol- the hydrolysisysis [92]. This [92 ].was This also was observed also observed for cyclic for cyclicphosphonates phosphonates [123]. [Ring123]. cleavage Ring cleavage also takes also takesplace placeduring during their alkaline their alkaline hydrolysis hydrolysis [109]. [109]. The alkalinealkaline hydrolysis hydrolysis of phenyl of phenyl methylphosphonate methylphosphonate and p-nitrophenyl and p-nitrophenyl methylphos- phonatemethylphosphonate (74) with the (74 application) with the ofapplication NaOH was of alsoNaOH studied was (Schemealso studied 43)[ 124(Scheme]. In this43) case,[124]. theIn this nucleophilic case, the nucleophilic attack of the attack hydroxide of the hydroxide ion occurs ion on occurs the phosphorus on the phosphorus atom of theatom P=O of the function. P=O function. The rate The of therate reaction of the reac increasedtion increased with the with increase the increase of the hydroxide of the hy- iondroxide concentration. ion concentration.

Molecules 2021, 26, x FOR PEER REVIEWScheme 43. Alkaline hydrolysis of aryl methylphosphonates 6666 usingusing NaOH.NaOH. 21 of 35

Dimethyl 4-toluenesulfonyloxymethylphosphonate4-toluenesulfonyloxymethylphosphonate (75 ()75 was) was treated treated with with 60% 60% pyridine- pyri- Molecules 2021, 26, x FOR PEER REVIEWH O at room temperature to give the monomethyl derivative at an 82% yield (Scheme 4421) [125 of 35]. dine-H2 2O at room temperature to give the monomethyl derivative at an 82% yield The(Scheme product 44) was[125]. a goodThe product phosphorylating was a good reagent phosphorylating to protect nucleosides. reagent to protect nucleosides.

Scheme 44. Preparation of methyl 4-toluenesulfonyloxymethylphosphonate (75) using aqueous pyridine. Scheme 44. Preparation of of methyl methyl 4-toluenesulfonyloxymethylphosphonate 4-toluenesulfonyloxymethylphosphonate (75) using(75) using aqueous aqueous pyridine. pyridine.The kinetics of the selective monohydrolysis of ethyl p-nitrophenyl chloro- methylphosphonateThe kinetics of the (77 selective) were monohydrolysisstudied in micellar of ethyl solutionsp-nitrophenyl of a cationic chloromethylphos- surfactant phonate(SchemeThe ( 45)77kinetics) were[126,127]. studiedof the in selective micellar solutionsmonohydrolysis of a cationic of surfactant ethyl p-nitrophenyl (Scheme 45) [126chloro-,127]. methylphosphonate (77) were studied in micellar solutions of a cationic surfactant (Scheme 45) [126,127].

Scheme 45. Alkaline hydrolysis hydrolysis of of ethyl ethyl p-nitrophenylp-nitrophenyl chloromethylphosphonate chloromethylphosphonate (77) ( in77 )micellar in micel- larsolutions. solutions. Scheme 45. Alkaline hydrolysis of ethyl p-nitrophenyl chloromethylphosphonate (77) in micellar In summary, the temperature, the solvent and the pH applied have a signiﬁcant solutions.In summary, the temperature, the solvent and the pH applied have a significant im- impactpact on onthe the course course of ofthe the alkaline alkaline hydrolysis. hydrolysis. Considering Considering the the effect effect of of the the C-substituents attached to the P atom, the reactivity of the phosphonates decreases with increasing steric attachedIn summary, to the P atom, the temperature, the reactivity the of solventthe phosphonates and the pH decreases applied havewith aincreasing significant steric im- congestion, and increases due to the effect of electron-withdrawing substituents (e.g., in congestion,pact on the courseand increases of the alkaline due to thehydrolysis. effect of Consideringelectron-withdrawing the effect ofsubstituents the C-substituents (e.g., in diethyl chloromethylphosphonate compared to diethyl methylphosphonate). Regarding diethylattached chloromethylphosphonate to the P atom, the reactivity compared of the phosphonates to diethyl methylphosphonate). decreases with increasing Regarding steric thecongestion, effect of andthe ORincreases function, due electron-withdrawingto the effect of electron-withdrawing R groups (e.g., NOsubstituents2Ph) increase (e.g., the in ratediethyl of thechloromethylphosphonate reaction. It is also noteworthy compared that to the diethyl hydrolysis methylphosphonate). of aryl esters is fasterRegarding than thatthe effect of their of aliphaticthe OR function, counterparts. electron-withdrawing R groups (e.g., NO2Ph) increase the rate of the reaction. It is also noteworthy that the hydrolysis of aryl esters is faster than 4.that Dealkylation of their aliphatic counterparts. 4.1. Dealkylation of Phosphinates 4. DealkylationIn the case of certain ester groups, a high temperature treatment may also be effective to4.1. cleave Dealkylation the O-C of bond. Phosphinates This is exemplified by the pyrolysis of diphenylphosphinates (30) with Inbranched the case alkyl of certain groups, ester affording groups, athe high corresponding temperature acid treatment quantitatively may also (Scheme be effective 46) [46].to cleave This the transformation O-C bond. This required is exemplified a treatm byent the at pyrolysis120–335 °C of diforphenylphosphinates 15 min, leaving diphe- (30) nylphosphinicwith branched acidalkyl ( 9groups,) in a solid affording form. Thethe coolefinrresponding that was acid liberated quantitatively departed (Schemeas a gas. 46) [46]. This transformation required a treatment at 120–335 °C for 15 min, leaving diphenylphosphinic acid (9) in a solid form. The olefin that was liberated departed as a gas.

Scheme 46. Pyrolysis of various alkyl diphenylphosphinates (30).

SchemeDealkylations 46. Pyrolysis are of various most often alkyl performed diphenylphosphinates using chemical (30). agents, such as trimethylsilyl halides (TMSX). Following the fission, there is need for a treatment with water or methanol toDealkylations form the corresponding are most often acid performed [28]. A usingmethyl-heptylphosphinic chemical agents, such acid as trimethylsilyl analogue of halides (TMSX). Following the fission, there is need for a treatment with water or methanol to form the corresponding acid [28]. A methyl-heptylphosphinic acid analogue of

Molecules 2021, 26, x FOR PEER REVIEW 21 of 35

Scheme 44. Preparation of methyl 4-toluenesulfonyloxymethylphosphonate (75) using aqueous pyridine.

The kinetics of the selective monohydrolysis of ethyl p-nitrophenyl chloromethylphosphonate (77) were studied in micellar solutions of a cationic surfactant (Scheme 45) [126,127].

Scheme 45. Alkaline hydrolysis of ethyl p-nitrophenyl chloromethylphosphonate (77) in micellar solutions.

In summary, the temperature, the solvent and the pH applied have a significant im- Molecules 2021, 26, 2840 pact on the course of the alkaline hydrolysis. Considering the effect of the C-substituents20 of 33 attached to the P atom, the reactivity of the phosphonates decreases with increasing steric congestion, and increases due to the effect of electron-withdrawing substituents (e.g., in diethyl chloromethylphosphonate compared to diethyl methylphosphonate). Regarding the effect of the OR function, electron-withdrawing R groups (e.g., NO2Ph) increase the the effect of the OR function, electron-withdrawing R groups (e.g., NO2Ph) increase the rate of the reaction. It is also noteworthy that the hydrolysis of aryl esters is faster than that rate of the reaction. It is also noteworthy that the hydrolysis of aryl esters is faster than of their aliphatic counterparts. that of their aliphatic counterparts. 4. Dealkylation 4.4.1. Dealkylation Dealkylation of Phosphinates 4.1. DealkylationIn the case of Phosphinates certain ester groups, a high temperature treatment may also be effective toIn the cleave case the of certain O-C bond. ester Thisgroups, is exempliﬁed a high temperature by the pyrolysistreatment ofmay diphenylphosphi- also be effective tonates cleave (30 )the with O-C branched bond. This alkyl is exemplified groups, affording by the pyrolysis the corresponding of diphenylphosphinates acid quantitatively (30) (Schemewith branched 46) [46 alkyl]. This groups, transformation affording required the corresponding a treatment acid at 120–335 quantitatively◦C for 15(Scheme min, leav- 46) [46].ing diphenylphosphinic This transformation acid required (9) in aa solidtreatm form.ent at The 120–335 oleﬁn that°C for was 15 liberated min, leaving departed diphe- as nylphosphinica gas. acid (9) in a solid form. The olefin that was liberated departed as a gas.

Scheme 46. Pyrolysis of various alkyl diphenylphosphinates (30). Molecules 2021, 26, x FOR PEER REVIEW 22 of 35 Molecules 2021, 26, x FOR PEER REVIEW 22 of 35 Dealkylations are most often performed using chemical agents, such as trimethylsilyl halides (TMSX). FollowingFollowing thethe ﬁssion,fission, there there is is need need for for a a treatment treatment with with water water or or methanol metha- nolto form to form the corresponding the corresponding acid [ 28acid]. A [28]. methyl-heptylphosphinic A methyl-heptylphosphinic acid analogue acid analogue of valproic of valproicacid (80) acid was ( prepared,80)) waswas prepared,prepared, in the hope inin thethe of its hopehope bioactivity. ofof itsits bioabioa Inctivity.ctivity. the ﬁnal InIn stepthethe finalfinal of the stepstep synthesis, ofof thethe syn-syn- the thesis,resultingthesis, thethe ethyl resultingresulting ester ethylethyl was cleaved esterester waswas by cleavedcleaved trimethylsilyl byby trimethylsilyltrimethylsilyl bromide (TMSBr) bromidebromide to (TMSBr)(TMSBr) give the targettoto givegive acid thethe target(target80) (Scheme acidacid ((80 47)) (Scheme)[(Scheme128]. The 47)47) exact [128].[128]. conditions TheThe exactexact wereconditionsconditions not reported. werewere notnot reported.reported.

Scheme 47. Dealkylation of methyl-heptylphosphinate ( 7979)) using using TMSBr. TMSBr.

Another exampleexample is is the the conversion conversion of ethylofof ethylethyl divinylphosphinate divinylphosphinatedivinylphosphinate (81) to((81 the)) toto correspond- thethe corre-corre- spondingingsponding acid (83 acidacid) by ((83 treatment)) byby treatmenttreatment with TMSBr withwith TMSBrTMSBr followed followedfollowed by methanolysis byby methanolysismethanolysis (Scheme (Scheme(Scheme 48)[129 48)48)]. [129].[129].

Scheme 48. Preparation of divinylphosphinic acid (82) by ethyl ﬁssion with TMSBr. Scheme 48. Preparation of divinylphosphinic acid (8282)) byby ethylethyl fissionfission withwith TMSBr.TMSBr. In addition to trimethylsilyl bromide, the iodide derivative (TMSI) is also a suitable InIn additionaddition toto trimethylsilyltrimethylsilyl bromide,bromide, thethe ioiodide derivative (TMSI) isis alsoalso aa suitablesuitable dealkylating agent. Its application was demonstrated via the deethylation ofof aa cycliccyclic ethylethyl dealkylatingphosphinate agent. (83) (Scheme Its application 49)[130 ].was demonstrated via the deethylation of a cyclic ethyl phosphinate (83)) (Scheme(Scheme 49)49) [130].[130].

Scheme 49. Dealkylation of an 1-ethoxyphospholane oxide (8383)) usingusing TMSI.TMSI.

4.2. Dealkylation of Phosphonates Certain phosphonates may also decompose on heatingheating toto givegive thethe correspondingcorresponding ac-acids.ids. TheThe di-di-terttert-butyl-butyl estersesters (e.g.,(e.g., 85),), whichwhich maymay undergoundergo dealkylationdealkylation atat 8080 °C,°C, areare par-par- ticularlyticularly suitable.suitable. TheThe exactexact conditionsconditions werewere notnot reportedreported inin thethe exampleexample shownshown inin SchemeScheme 50 [79].

Scheme 50. Thermal dealkylation of a di-tert-tert-butyl vinylphosphonate (8585).).

The dealkylation of the esters (65)) maymay alsoalso taketake placeplace withwith thethe aidaid ofof variousvarious rea-reagents, most commonly with TMSX [131–136]. InIn thethe firstfirst step,step, thethe correspondingcorresponding bis-tri-bis-trimethylsilyl ester (87)) isis formed,formed, whichwhich providesprovides thethe correspondingcorresponding phosphonicphosphonic acidacid ((66))

Molecules 2021, 26, x FOR PEER REVIEW 22 of 35

valproic acid (80) was prepared, in the hope of its bioactivity. In the final step of the synthesis, the resulting ethyl ester was cleaved by trimethylsilyl bromide (TMSBr) to give the valproic acid (80) was prepared, in the hope of its bioactivity. In the final step of the syn- target acid (80) (Scheme 47) [128]. The exact conditions were not reported. thesis, the resulting ethyl ester was cleaved by trimethylsilyl bromide (TMSBr) to give the target acid (80) (Scheme 47) [128]. The exact conditions were not reported.

Scheme 47. Dealkylation of methyl-heptylphosphinate (79) using TMSBr. Scheme 47. Dealkylation of methyl-heptylphosphinate (79) using TMSBr. Another example is the conversion of ethyl divinylphosphinate (81) to the corresponding acid (83) by treatment with TMSBr followed by methanolysis (Scheme 48) [129]. Another example is the conversion of ethyl divinylphosphinate (81) to the corresponding acid (83) by treatment with TMSBr followed by methanolysis (Scheme 48) [129].

Scheme 48. Preparation of divinylphosphinic acid (82) by ethyl fission with TMSBr. Scheme 48. Preparation of divinylphosphinic acid (82) by ethyl fission with TMSBr. In addition to trimethylsilyl bromide, the iodide derivative (TMSI) is also a suitable dealkylating agent. Its application was demonstrated via the deethylation of a cyclic ethyl In addition to trimethylsilyl bromide, the iodide derivative (TMSI) is also a suitable Molecules 2021, 26, 2840 phosphinate (83) (Scheme 49) [130]. 21 of 33 dealkylating agent. Its application was demonstrated via the deethylation of a cyclic ethyl phosphinate (83) (Scheme 49) [130].

Scheme 49. Dealkylation of an 1-ethoxyphospholane oxide (83) using TMSI. Scheme 49. Dealkylation of an 1-ethoxyphospholane oxide (8383)) usingusing TMSI.TMSI. 4.2. Dealkylation of Phosphonates 4.2. Dealkylation of Phosphonates 4.2. DealkylationCertain phosphonates of Phosphonates may also decompose on heating to give the corresponding acids. TheCertain di-tert phosphonates-butyl esters may (e.g., also 85), decompose which may on undergo heating todealkylation give the corresponding at 80 °C, are acids. par- Certain phosphonates may also decompose on heating to give the corresponding ac- Theticularly di-tert suitable.-butyl esters The exact (e.g., conditions85), which were may undergonot reported dealkylation in the example at 80 ◦C, shown are particularly in Scheme ids. The di-tert-butyl esters (e.g., 85), which may undergo dealkylation at 80 °C, are par- suitable.50 [79]. The exact conditions were not reported in the example shown in Scheme 50[79]. ticularly suitable. The exact conditions were not reported in the example shown in Scheme 50 [79].

Scheme 50. Thermal dealkylation of a di-terttert--butylbutyl vinylphosphonate (85 ).). Molecules 2021, 26, x FOR PEER REVIEW 23 of 35 Molecules 2021, 26, x FOR PEER REVIEWScheme 50. Thermal dealkylation of a di-tert-butyl vinylphosphonate (85). 23 of 35 The dealkylationdealkylation ofof the the esters esters (65 (65) may) may also also take take place place with with the aidthe ofaid various of various reagents, rea- mostgents, commonly most commonly with TMSX with [ 131TMSX–136 [131–136].]. In the ﬁrst In step,the first the correspondingstep, the corresponding bis-trimethylsilyl bis-tri- esterThe (87) dealkylation is formed, which of the provides esters ( the65) correspondingmay also take phosphonicplace with the acid aid (66 of) onvarious treatment rea- methylsilylon treatment ester with ( 87water) is formed, or methanol. which This provides protocol, the illustratedcorresponding in Scheme phosphonic 51, may acid be con-(66) withongents, treatment water most or commonly with methanol. water with Thisor methanol. TMSX protocol, [131–136]. This illustrated protocol, In inthe Schemeillustrated first step, 51, in maythe Scheme corresponding be considered 51, may be tobis-tri- con- be a sidered to be a gentle and convenient method [79,137]. gentlesideredmethylsilyl and to be convenient ester a gentle (87) isand method formed, convenient [79 which,137 ].method provides [79,137]. the corresponding phosphonic acid (66)

Scheme 51. Dealkylation of diethyl alkylphosphonates (65) using TMSBr. Scheme 51. Dealkylation of diethyl alkylphosphonates (65) using TMSBr. Later on, the mechanism of the reaction was investigated, and it was found that Later on,on, thethe mechanism mechanism of of the the reaction reaction was was investigated, investigated, and itand was it found was thatfound TMSBr that TMSBr attacks the oxygen atom of the P=O function [138]. The sequence of the double attacksTMSBr theattacks oxygen the atomoxygen of the atom P=O of function the P=O [138 func]. Thetion sequence[138]. The of sequence the double of dealkylation the double dealkylation with TMSI is shown in Scheme 52 [139,140]. withdealkylation TMSI is with shown TMSI in Scheme is shown 52 [in139 Scheme,140]. 52 [139,140].

Scheme 52. Proposed mechanism for the double dealkylations withwith TMSI.TMSI. Scheme 52. Proposed mechanism for the double dealkylations with TMSI. The cleavage with trimethylsilyl chloride (TMSCl) is not an often-used procedure The cleavage with trimethylsilyl chloride (TMSCl) is not an often-used procedure [59]. This derivative is less reactive than TMSBr, and therefore requires a longer reaction [59]. This derivative is less reactive than TMSBr, and therefore requires a longer reaction time at a higher temperature. However, its lower cost and easier handling justifies its ap- time at a higher temperature. However, its lower cost and easier handling justifies its application. In a typical example, the mixture was heated up to 130–140 °C using three to plication. In a typical example, the mixture was heated up to 130–140 °C using three to four equivalents of TMSCl in chlorobenzene. The complete removal of the ester function four equivalents of TMSCl in chlorobenzene. The complete removal of the ester function took 8–36 h. The corresponding phosphonic acids (66) were obtained after hydrolysis took 8–36 h. The corresponding phosphonic acids (66) were obtained after hydrolysis (Scheme 53) [140]. (Scheme 53) [140].

Scheme 53. Double cleavage with TMSCl. Scheme 53. Double cleavage with TMSCl. The TMSC1 reagent can also be used in the preparation of PMEA/PMPA (90), which The TMSC1 reagent can also be used in the preparation of PMEA/PMPA (90), which are known as antiviral agents (Scheme 54) [141]. are known as antiviral agents (Scheme 54) [141].

Molecules 2021, 26, x FOR PEER REVIEW 23 of 35

on treatment with water or methanol. This protocol, illustrated in Scheme 51, may be considered to be a gentle and convenient method [79,137].

Scheme 51. Dealkylation of diethyl alkylphosphonates (65) using TMSBr.

Later on, the mechanism of the reaction was investigated, and it was found that TMSBr attacks the oxygen atom of the P=O function [138]. The sequence of the double dealkylation with TMSI is shown in Scheme 52 [139,140].

Molecules 2021, 26, 2840 22 of 33 Scheme 52. Proposed mechanism for the double dealkylations with TMSI.

The cleavage with trimethylsilyl chloride (TMSCl) is not an often-used procedure [59]. TheThiscleavage derivative with is less trimethylsilyl reactive than chloride TMSBr, (TMSCl) and therefore is not an requires often-used a longer procedure reaction [59]. Thistime derivativeat a higher is temperature. less reactive thanHowever, TMSBr, its and lower therefore cost and requires easier a handling longer reaction justifies time its atap- a plication.higher temperature. In a typical However, example, its the lower mixture cost andwas easier heated handling up to 130–140 justiﬁes °C its application.using three Into foura typical equivalents example, of the TMSCl mixture in chlorobenzene. was heated upto The 130–140 complete◦C using removal three of to the four ester equivalents function tookof TMSCl 8–36 inh. chlorobenzene.The corresponding The completephosphonic removal acids of(66 the) were ester obtained function tookafter8–36 hydrolysis h. The (Schemecorresponding 53) [140]. phosphonic acids (66) were obtained after hydrolysis (Scheme 53)[140].

Scheme 53. Double cleavage with TMSCl.

Molecules 2021, 26, x FOR PEER REVIEW 24 of 35 The TMSC1 reagent can also be usedused inin thethe preparationpreparation ofof PMEA/PMPAPMEA/PMPA (90), which are known as antiviral agents (Scheme 5454))[ [141].141].

Scheme 54. Preparation of two antiviral agents ((9090).).

McKenna compared the reactivity of TMSCl and TMSBr,TMSBr, andand foundfound thatthat whilewhile thethe dealkylation with TMSCl, in most cases, waswas notnot completecomplete withinwithin 1–91–9 days,days, thethe reactionreaction withwith thethe bromidebromide derivativederivative waswas completecomplete withinwithin 1–31–3 hh (Table(Table6 )[6) 57[57].].

Table 6.6. ComparisonComparison ofof thethe reactivityreactivity ofof TMSClTMSCl andand TMSBr.TMSBr. Dialkyl Phosphonate 行 Dialkyl Phosphonate0 TMSCl TMSBr RP(O)(OR )2 TMSCl TMSBr RP(O)(OR’)2 Temp. Time Yields Temp. Time Yields RR0 Equiv. Temp.行 Time行 Yields行Equiv. Temp.行 Time行 Yields行 R R’ Equiv. (◦C) (days) (%) Equiv. (◦C) (h) (%) (°C) (days) (%) (°C) (h) (%) CH =CH Et 2.7 69–72 5 94 1.5 25 1.2 >99 2CH2=CH Et 2.7 69–72 5 94 1.5 25 1.2 >99 PhCH2 Et 2.2 40 1 <5 1.7 25 2.0 >99 PhCH2 Et 2.2 40 1 <5 1.7 25 2.0 >99 EtOCH2CH2 Et 2.9 40 1 <10 1.7 25 0.7 >99 EtOCHCl3C2CH2 EtEt 5.42.9 >72 40 8 1 13 <10 1.5 1.7 61–69 25 2.7 0.7 >99>99 PhC(O)Cl3C MeEt 1.95.4 25>72 98 1213 1.51.5 2561–69 1.72.7 >99>99 PhC(O) Me 1.9 25 9 12 1.5 25 1.7 >99 The dealkylation reactions could be promoted by the addition of sodium iodide as a co-reagentThe dealkylation to TMSCl [ 142reactions]. In a fewcould cases, be promoted the corresponding by the addition phosphonic of sodium acids iodide (66) were as a obtainedco-reagent in to good TMSCl yields [142]. after In treatment a few case withs, the this corresponding mixture of reagents phosphonic at room acids temperature (66) were forobtained 15–60 in min good (Scheme yields 55 after)[143 treatment]. with this mixture of reagents at room temperature for 15–60 min (Scheme 55) [143].

Scheme 55. Double dealkylation using TMSCl in the presence of sodium iodide.

Using lithium iodide, dialkyl phosphonates were cleaved under milder conditions [144]. In most of the cases, TMSBr was used in the dealkylations [145–171]. The conversion of phosphonates to the corresponding acids plays an important role in the synthesis of drugs. This is illustrated by the last step of the synthesis of Tenofovir (90) (Scheme 56) [172]. TMSCl/NaBr was applied in the preparation of other anti-HIV agents as well [173].

Molecules 2021, 26, x FOR PEER REVIEW 24 of 35

Scheme 54. Preparation of two antiviral agents (90).

McKenna compared the reactivity of TMSCl and TMSBr, and found that while the dealkylation with TMSCl, in most cases, was not complete within 1–9 days, the reaction with the bromide derivative was complete within 1–3 h (Table 6) [57].

Table 6. Comparison of the reactivity of TMSCl and TMSBr.

Dialkyl Phosphonate行 TMSCl TMSBr RP(O)(OR’)2 Temp.行 Time行 Yields行 Temp.行 Time行 Yields行 R R’ Equiv. Equiv. (°C) (days) (%) (°C) (h) (%) CH2=CH Et 2.7 69–72 5 94 1.5 25 1.2 >99 PhCH2 Et 2.2 40 1 <5 1.7 25 2.0 >99 EtOCH2CH2 Et 2.9 40 1 <10 1.7 25 0.7 >99 Cl3C Et 5.4 >72 8 13 1.5 61–69 2.7 >99 PhC(O) Me 1.9 25 9 12 1.5 25 1.7 >99

The dealkylation reactions could be promoted by the addition of sodium iodide as a co-reagent to TMSCl [142]. In a few cases, the corresponding phosphonic acids (66) were Molecules 2021, 26, 2840 23 of 33 obtained in good yields after treatment with this mixture of reagents at room temperature for 15–60 min (Scheme 55) [143].

Scheme 55. Double dealkylation using TMSCl in the presence of sodium iodide.

Using lithiumlithium iodide,iodide, dialkyl dialkyl phosphonates phosphonates were were cleaved cleaved under under milder milder conditions conditions [144]. [144].In most In ofmost the cases,of the TMSBrcases, TMSBr was used was in used the dealkylations in the dealkylations [145–171 [145–171].]. The conversion ofof phosphonatesphosphonates to to the the corresponding corresponding acids acids plays plays an an important important role role in the synthesis of drugs. This is illustrated by the last step of the synthesis of Tenofovir (90) Molecules 2021, 26, x FOR PEER REVIEWin the synthesis of drugs. This is illustrated by the last step of the synthesis of Tenofovir25 of 35 Molecules 2021, 26, x FOR PEER REVIEW 25 of 35 ((Scheme90) (Scheme 56)[ 17256)]. [172]. TMSCl/NaBr TMSCl/NaBr was appliedwas applied in the in preparation the preparation of other of anti-HIVother anti-HIV agents as well [173]. agents as well [173].

Scheme 56. Preparation of an anti-HIV agent (9090)) byby dealkylationdealkylation withwith TMSCl/NaBr.TMSCl/NaBr.TMSCl/NaBr.

i ii 2 88 The double cleavagecleavage ofof thethe P(O)(OP(O)(O Pr)22 functionfunctionfunction inin in aa a seriesseries ofof diisopropyl diisopropyl esters esters ( (88)) ◦ waswas performedperformed withwith TMSBrTMSBr atat 6060 °CC for 4–24 h. Using three equivalents of TMSBr, yieldsyields of around 80% were reported. A work-up including a treatment with NaOH and methanol gave the mono-Na saltsalt ofof thethe phosphonicphosphonic acidacid ((9191))) (Scheme(Scheme(Scheme 5757)57))[ [174].[174].174].

Scheme 57. Dealkylation of a series of diisopropyl estersesters ((8888)) withwith TMSBr.TMSBr. Certain analogues of purine-based phosphonic acids are able to inhibit the FBSase Certain analogues of purine-based phosphonic acids are able to inhibit the FBSase enzyme, making them effective in the treatment of type 2 diabetes. During the synthesis enzyme, making them effective in the treatmentt ofof typetype 22 diabetes.diabetes. DuringDuring thethe synthesissynthesis of these type of compounds, the cleavage of the ester group was performed with TMSBr of these type of compounds, thethe cleavagecleavage ofof thethe esterester grgroup was performed with TMSBr (Scheme 58)[175]. (Scheme(Scheme 58)58) [175].[175]. TMSBr may also be used in the dealkylation of metal complexes (95) (Scheme 59)[176]. In addition to TMSBr, boron tribromide was also proven to be an effective dealkylating reagent [177]. In this case, the reaction resulted in the formation of borophosphonate oligomers [–O–PR(O–)–O–B(O–)(O–)]n, along with the alkyl bromide by-product [53]. The methanolysis of the intermediate led to free phosphonic acid (66) and B(OMe)3 (Scheme 60).

Scheme 58. Preparation of a purine-based phosphonic acid (93)) usingusing TMSBr.TMSBr.

TMSBr may also be used in the dealkylation of metal complexes (95)) (Scheme(Scheme 59)59) [176].[176].

Scheme 59. Modification of a complex (94)) byby doubledouble dealkylation.dealkylation.

Molecules 2021, 26, x FOR PEER REVIEW 25 of 35

Scheme 56. Preparation of an anti-HIV agent (90) by dealkylation with TMSCl/NaBr.

The double cleavage of the P(O)(OiPr)2 function in a series of diisopropyl esters (88) Scheme 56. Preparation of an anti-HIV agent (90) by dealkylation with TMSCl/NaBr. was performed with TMSBr at 60 °C for 4–24 h. Using three equivalents of TMSBr, yields of around 80% were reported. A work-up including a treatment with NaOH and methanol The double cleavage of the P(O)(OiPr)2 function in a series of diisopropyl esters (88) gave the mono-Na salt of the phosphonic acid (91) (Scheme 57) [174]. was performed with TMSBr at 60 °C for 4–24 h. Using three equivalents of TMSBr, yields of around 80% were reported. A work-up including a treatment with NaOH and methanol gave the mono-Na salt of the phosphonic acid (91) (Scheme 57) [174].

Scheme 57. Dealkylation of a series of diisopropyl esters (88) with TMSBr.

Certain analogues of purine-based phosphonic acids are able to inhibit the FBSase Scheme 57. Dealkylation of a series of diisopropyl esters (88) with TMSBr. enzyme, making them effective in the treatment of type 2 diabetes. During the synthesis of these type of compounds, the cleavage of the ester group was performed with TMSBr Certain analogues of purine-based phosphonic acids are able to inhibit the FBSase (Scheme 58) [175]. enzyme, making them effective in the treatment of type 2 diabetes. During the synthesis Molecules 2021, 26, 2840 24 of 33 of these type of compounds, the cleavage of the ester group was performed with TMSBr (Scheme 58) [175].

Scheme 58. Preparation of a purine-based phosphonic acid (93) using TMSBr.

TMSBr may also be used in the dealkylation of metal complexes (95) (Scheme 59) Scheme 58.Scheme Preparation 58. Preparation of a purine-based of a purine-based phosphonic phosphonic acid (93) using acid (93 TMSBr.) using TMSBr. [176]. TMSBr may also be used in the dealkylation of metal complexes (95) (Scheme 59) Molecules 2021, 26, x[176]. FOR PEER REVIEW 26 of 35

In addition to TMSBr, boron tribromide was also proven to be an effective dealkylating reagent [177]. In this case, the reaction resulted in the formation of borophosphonate oligomers [–O–PR(O–)–O–B(O–)(O–)]n, along with the alkyl bromide by-product [53]. The oligomers [–O–PR(O–)–O–B(O–)(O–)]n, along with the alkyl bromide by-product [53]. The methanolysis of the intermediate led to free phosphonic acid (66) and B(OMe)3 (Scheme Scheme 59. ModificationModiﬁcation of a complex ( 94) by double dealkylation. 60).

Scheme 59. Modification of a complex (94) by double dealkylation.

Scheme 60. Cleavage of the alkoxy groups of phosphonates by BBr3. Scheme 60. Cleavage of the alkoxy groups of phosphonates by BBr33.

In specialspecial cases,cases, a cationcation exchangeexchange resinresin was usedused asas aa catalystcatalyst inin dealkylationsdealkylations ◦ (Scheme(Scheme 6161))[ [178].178]. The phenylphosphonates ( (88)) were reacted at 4040 °CC for aa prolongedprolonged reaction time to affordafford phenylphosphonicphenylphosphonic acid ((66)) inin variablevariable yields,yields, dependingdepending onon thethe nature of the R group.

Scheme 61. The use of cation exchange resin in dealkylations. The dealkylation of diethyl ethylphosphonate (65) was performed using γ-alumina The dealkylation of diethyl ethylphosphonate (65) was performed using γ-alumina and silica gel. At a temperature of 300 ◦C, the cleavage of the P-C bond also occurred in and silica gel. At a temperature of 300 °C, the cleavage of the P-C bond also occurred in addition to the desired ﬁssion of the C-O bond (Scheme 62)[179]. addition to the desired fission of the C-O bond (Scheme 62) [179]. The monodealkylation of phosphonates (98) was also elaborated using sodium iodide in polar solvents (Scheme 63)[150,180–182]. The monodealkylation of phosphonates (100) was also performed under phase transfer catalytic conditions (Scheme 64)[183]. In this case, triethylbenzylammonium bromide or triethylbenzylammonium chloride (TEBAB or TEBAC, respectively) was applied as the catalyst in the dealkylation performed at reﬂux for 24–150 h.

Scheme 62. Catalytic dealkylation of diethyl ethylphosphonate (65) using γ-alumina and silica gel.

The monodealkylation of phosphonates (98) was also elaborated using sodium iodide in polar solvents (Scheme 63) [150,180–182].

Scheme 63. Monodealkylation of phosphonates using NaI.

The monodealkylation of phosphonates (100) was also performed under phase transfer catalytic conditions (Scheme 64) [183]. In this case, triethylbenzylammonium bromide

Molecules 2021, 26, x FOR PEER REVIEW 26 of 35

Molecules 2021, 26, x FOR PEER REVIEW 26 of 35 In addition to TMSBr, boron tribromide was also proven to be an effective dealkylating reagent [177]. In this case, the reaction resulted in the formation of borophosphonate oligomers [–O–PR(O–)–O–B(O–)(O–)]n, along with the alkyl bromide by-product [53]. The In addition to TMSBr, boron tribromide was also proven to be an effective dealkylat- methanolysis of the intermediate led to free phosphonic acid (66) and B(OMe)3 (Scheme ing reagent [177]. In this case, the reaction resulted in the formation of borophosphonate 60). oligomers [–O–PR(O–)–O–B(O–)(O–)]n, along with the alkyl bromide by-product [53]. The methanolysis of the intermediate led to free phosphonic acid (66) and B(OMe)3 (Scheme 60).

Scheme 60. Cleavage of the alkoxy groups of phosphonates by BBr3.

In special cases, a cation exchange resin was used as a catalyst in dealkylations Scheme 60. Cleavage of the alkoxy groups of phosphonates by BBr3. (Scheme 61) [178]. The phenylphosphonates (88) were reacted at 40 °C for a prolonged reaction time to afford phenylphosphonic acid (66) in variable yields, depending on the In special cases, a cation exchange resin was used as a catalyst in dealkylations nature of the R group. (Scheme 61) [178]. The phenylphosphonates (88) were reacted at 40 °C for a prolonged reaction time to afford phenylphosphonic acid (66) in variable yields, depending on the nature of the R group.

Scheme 61. The use of cation exchange resin in dealkylations.

The dealkylation of diethyl ethylphosphonate (65) was performed using γ-alumina Scheme 61. The use of cation exchange resin in dealkylations. and silica gel. At a temperature of 300 °C, the cleavage of the P-C bond also occurred in addition to the desired fission of the C-O bond (Scheme 62) [179]. The dealkylation of diethyl ethylphosphonate (65) was performed using γ-alumina Molecules 2021, 26, 2840 25 of 33 and silica gel. At a temperature of 300 °C, the cleavage of the P-C bond also occurred in addition to the desired fission of the C-O bond (Scheme 62) [179].

Scheme 62. Catalytic dealkylation of diethyl ethylphosphonate (65) using γ-alumina and silica gel.

The monodealkylation of phosphonates (98) was also elaborated using sodium io- Scheme 62. Catalytic dealkylation of diethyl ethylphosphonate (65) usingusing γ-alumina andand silicasilica gel.gel. dide in polar solvents (Scheme 63) [150,180–182]. The monodealkylation of phosphonates (98) was also elaborated using sodium iodide in polar solvents (Scheme 63) [150,180–182].

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or triethylbenzylammonium chloride (TEBAB or TEBAC,TEBAC, respectively)respectively) waswas appliedapplied asas thethe Scheme 63. Monodealkylation of phosphonates using NaI. catalystScheme 63.in theMonodealkylation dealkylation performedof phosphonates at reflux using for NaI. 24–150 h.

The monodealkylation of phosphonates (100) was also performed under phase trans- Scheme 63. Monodealkylation of phosphonates using NaI. fer catalytic conditions (Scheme 64) [183]. In this case, triethylbenzylammonium bromide The monodealkylation of phosphonates (100) was also performed under phase transfer catalytic conditions (Scheme 64) [183]. In this case, triethylbenzylammonium bromide

Scheme 64. Monodealkylation of phosphonates ( 100)) under under phase-transfer phase-transfer catalyticcatalytic conditions.conditions.

◦ Diethyl phosphonates could also be monodealkylatedmonodealkylated at 80–100 °CC for goodgood yieldsyields using lithium lithium bromide bromide or or chloride chloride [184]. [184 ].There There isis anan is exampleexample an example ofof thethe of useuse the ofof use lithiumlithium of lithium triethyl-triethyl- tri- borohydrideethylborohydride as the as monodealkylating the monodealkylating agent agentin the inpreparation the preparation of GABA of GABA analogue analogue phosphonicphosphonic acids acids (102) ( (Scheme102) (Scheme 65) [185]. 65)[ 185].

Scheme 65. Selective monodealkylation using LiHBEt3.. Scheme 65. Selective monodealkylation using LiHBEt3. In a few cases, the dealkylation could also be accomplished with amines, e.g., the In a few cases, the dealkylation could also be accomplished with amines, e.g., the monodealkylation of H-phosphonates was performed with tert-butylamine [54,55], but monodealkylation of HH-phosphonates was performed with tert-butylamine [54,55], but hydrazine could also be applied as a dealkylating agent [186]. hydrazine could also be applied as a dealkylating agent [186]. 5. Conclusions 5. Conclusions P-acids have a significant role among drugs. Additionally, they have applications as P-acids have a significant role among drugs. Additionally, they have applications as herbicidesP-acids and have flame a significant retardants role as well. among Hydrolysis drugs. Additionally, is the most frequently they have usedapplications method as to herbicides and flame retardants as well. Hydrolysis is the most frequently used method herbicidesprepare P-acids and flame that mayretardants be catalyzed as well. by Hydrolysis acids and bases.is the most Comparing frequently the twoused methods, method to prepare P-acids that may be catalyzed by acids and bases. Comparing the two methods, toit canprepare be said P-acids that thethat alkaline may be catalyzed hydrolysis by takes acids place and bases. faster, Comparing and is less corrosive, the two methods, but it is it can be said that the alkaline hydrolysis takes place faster, and is less corrosive, but it is itrealized can be insaid two that steps. the alkaline The Na hydrolysis salt is formed takes in place the first faster, step, and followed is less corrosive, by the liberation but it is realized in two steps. The Na salt is formed in the first step, followed by the liberation of realizedof the free in two acid. steps. While The the Na acid-catalyzed salt is formed hydrolysisin the first step, may followed involve theby the cleavage liberation of the of the free acid. While the acid-catalyzed hydrolysis may involve the cleavage of the P-O theP-O free bond acid. (A AcWhile2 mechanism) the acid-catalyzed and that ofhydrolysis the C-O may bond involve (AAl1 mechanism) the cleavage as of well, the P-O the bond (AAc2 mechanism) and that of the C-O bond (AAl1 mechanism) as well, the alkaline bondalkaline (AAc hydrolysis2 mechanism) takes and place that viaof the the C-O cleavage bond of(AAl P-O1 mechanism) bond. This as explains well, the whyalkaline the hydrolysis takes place via the cleavage of P-O bond. This explains why the isopropyl ester reacts faster than the methyl ester under acidicidic conditions,conditions, whilewhile inin thethe base-catalyzedbase-catalyzed process, the former reacts considerably slower. The course of the reactions may be influenced by various factors, such as the temperature, solvent, pH, and the substituents attached to the phosphorus atom. The steric hindrance decreases the reaction rate, while the electron-withdrawing effects either in the C- oror OC-substituentsOC-substituents attachedattached toto thethe PP atomatom increaseincrease thethe reactivity.reactivity. AnotherAnother memethod to convert the esters to P-acids is cleavage by trimethylsilyl halides. This approach is selective and requires milder conditions. In addition to hydrolysis under conventional conditions,, MW-assistedMW-assisted variationsvariations werewere alsoalso elabo-elaborated, giving environmentally friendlyly andand efficientefficient accomplishments.accomplishments. Through the examples discussed, it was shown that the hydrolysis of P-esters has not yet been explored fully, and generally that the reaction conditions have not been optimized. Despite these facts, especially on the basis of our own findings, this review may help us to get closer to a better understanding of this area of phosphorus chemistry. We

Molecules 2021, 26, 2840 26 of 33

isopropyl ester reacts faster than the methyl ester under acidic conditions, while in the base- catalyzed process, the former reacts considerably slower. The course of the reactions may be influenced by various factors, such as the temperature, solvent, pH, and the substituents attached to the phosphorus atom. The steric hindrance decreases the reaction rate, while the electron-withdrawing effects either in the C- or OC-substituents attached to the P atom increase the reactivity. Another method to convert the esters to P-acids is cleavage by trimethylsilyl halides. This approach is selective and requires milder conditions. In addition to hydrolysis under conventional conditions, MW-assisted variations were also elaborated, giving environmentally friendly and efficient accomplishments. Through the examples discussed, it was shown that the hydrolysis of P-esters has not yet been explored fully, and generally that the reaction conditions have not been optimized. Despite these facts, especially on the basis of our own findings, this review may help us to get closer to a better understanding of this area of phosphorus chemistry. We advise the performance of the hydrolyses under acidic conditions using 0.5 mL of cc. HCl in 1 mL water to each 2 mmol of the phosphinate, or to each 1 mmol of the phosphonate.

Funding: This project was funded by the National Research, Development and Innovation Office (K134318). Conflicts of Interest: The authors declare no conflict of interest.

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