Chemistry of Phosphorylated Formaldehyde Derivatives. Part I

The underinvestigated derivatives of unstable phosphorylated formaldehyde acetals and some of the structurally related compounds, such as thioacetals, aminonitriles, aminomethylphosphinoyl compounds, are considered. Separately considered are halogen aminals of phosphorylated formaldehyde, acetals of phosphorylated formaldehyde of H-phosphinate-type and a phosphorylated gem-diol of formaldehyde. Synthetic methods, chemical properties and examples of practical applications are given.


Introduction
Among organophosphorus compounds, α-phosphorylated carbonyl compounds stand out by the capacity of cleavage of phosphorus-carbon bond under mild conditions when reacted with nucleophiles [1][2][3][4][5]. The cleavage of phosphorus-carbon bond may proceed spontaneously as well. At the same time, α-oxoalkylphosphinoyl compounds also retain properties inherent in carbonyl compounds, for example, they undergo cross aldol condensation.

Chemistry of Phosphorylated Formaldehyde Acetals 13
Chemistry of phosphorylated formaldehyde acetals 13 started as a chemistry of dialkyl (dialkoxymethyl)phosphonates 33 due to their more ready availability as compared with the analogs-N,N,N',N'-tetraalkyl(dialkoxymethyl)phosphondiamides 48, dialkyl (dialkoxymethyl)-phosphine oxides 49 or diphenyl(dialkoxymethyl)phosphine oxide 50. Many types of acetals are known to date, but their chemical properties are still insufficiently studied, although they are more studied than the other derivatives of phosphorylated formaldehyde.

Chemical Properties of Phosphorylated Formaldehyde Acetals 13
The chemistry of phosphorylated formaldehyde acetals 13 was initially developed for the most part as a chemistry of available dialkyl (dialkoxymethyl)phosphonates 33. Therefore the properties of acetals as a separate type of organophosphorus compounds were studied mainly by the examples of compounds 33 whose reactivity is affected by the presence of both phosphorus ester and acetal groups.

92
The heating of a solution of diethyl (dialkoxymethyl)phosphonate 93 in absolute ethanol with sodium ethoxide (NaOEt) leads to dealkylation of one of the ethoxy groups by phosphorus atom to form ethyl sodium (dialkoxymethyl)phosphonate 94, which produces the free acid 95 on acidification [95]. Heating of 93 with sodium iodide NaI leads to the same result [93]. The reaction of ethyl sodium (diethoxymethyl)phosphonate (96) with electrophilic reagents brings about the formation of phosphonates 97 with different substituents at the phosphorus atom [95]  Acids 95 show typical properties of hydroxy compounds. Using as example ethyl (diethoxymethyl)phosphonic acid (98) it is shown that they react with diazomethane and thionyl chloride. The reaction products are ethyl methyl (diethoxymethyl)phosphonate (99) and ethyl (diethoxymethyl)phosphonic chloride (100) [95], which reacts with phenylmagnesium bromide in tetrahydrofuran to produce ethyl phenyl(diethoxymethyl)phosphinate (101)  The acetal group of compounds 13 is rather stable to the action of co-reactants. Nonetheless, a series of transformations of phosphorylated formaldehyde acetals (33) that involves dialkoxyacetal group is described.
Dialkyl (1,3-benzodithiolylmethyl)phosphonates 115 were prepared for the first time by the reaction of 1,3-benzodithiolyl tetrafluoroborate with 58 in the presence of NaI [103]. The method is used at present without changes [116]

Chemical Properties of Diphosphinoyl N,N-Dialkylaminomethanes 16
The chemical properties of this type of organophosphorus compounds are studied insufficiently and almost exclusively by the example of tetraethyl (N,N-dimethylaminomethyl)diphosphonate (161). Their properties are attributable to the presence of both an amino group and disubstituted phosphoryl groups.

General Chemical Properties of Phosphorylated Formaldehyde Acetals 13 and Structurally
Related Compounds 14-16

Cleavage of Phosphorus-Carbon Bond under the Action of Acids and Acidic Reagents
The general property of phosphorylated formaldehyde acetals 13 and structurally related compounds 14-16 is the possibility of phosphorus-carbon bond cleavage under the action of acids and acidic reagents [24,77,95,98], organic reagents [19,119], and bases [37,127,128].

Alkylation (Acylation) of the Formacetal Carbon Atom
Dialkyl (dialkoxymethyl)phosphonates 33 produce no stable phosphorylated carbanion 206 when reacted with bases (no metallation occurs, even under the action of tert-butyllithium (t-BuLi), which provides no possibility for further alkylation and acylation of the formacetal group [23,132]  This fact was explained by insufficient stabilization of the negative charge of carbanion on the two oxygen atoms in the α-position [23]. However, it was shown in 1983 [133] that, in contrast to phosphonates 33, diphenyl(dialkoxymethyl)phosphine oxides 50 produce phosphorylated anions 195 at −110 °C that undergo metallation. The reason for the stability of the lithium derivatives of phosphine oxides 50 is the ability of diphenylphosphinoyl group to delocalize the negative charge of carbanion 195 [20,134] (Scheme 58). By the example of anion 207 of diphenyl(dimethoxy-methyl)phosphine oxide (208), it was shown that it is rather stable to subsequent alkylation with alkyl halides and acylation with benzoyl chloride [20]. Similarly, according to 1 H-NMR spectroscopy, the methanolysis of diphenyl[(1,1-dialkoxy)nonan-1-yl)phosphine oxide (212) in the presence of trifluoroacetic acid leads to 1,1,1-trimethoxynonane (213) in 65% yield [20].
Nonetheless, the storage of a solution of lithiated anion 207 for two hours even at −110 °C causes the cleavage of phosphorus-carbon bond (see Scheme 58).

Horner Reaction
In 1958 and 1959 L. Horner and co-authors reported their discovery of a new reaction [137,138] that they named as "P=O-activated olefination". The authors showed that the reaction of alkyl(diphenyl)phosphine oxides 224 and dialkyl alkylphosphonates 225 with aldehydes and ketones in the presence of strong bases produce olefins 226 (Scheme 69). Key reaction intermediates-lithium derivatives of carbanion of the initial phosphinoyl compounds 227 and β-phosphorylated hydroxy derivatives 228 were identified on the example reaction of benzyl(diphenyl)phosphine oxide (229) with benzaldehyde in the presence of phenyllithium [138]. The reaction has a number of advantages in comparison with similar reaction of phosphorus ylides previously described by L. Wittig [139] where ketones are difficult to react, whereas both aldehydes and ketones undergo the Horner reaction. It was further shown that Horner reaction has a larger synthetic potential and is applicable for the synthesis of other types of organic compounds, for example, allenes, cyclopropanes, terminal [140] and disubstituted alkynes [132]. The involvement of phosphonates functionalized at the α-position with dialkylamino, alkoxy or alkylthio groups in the reaction leads to enamines, vinyl ethers [132,[141][142][143] and vinyl thioethers [141,143]. Their subsequent hydrolysis affords aldehydes and ketones with elongated hydrocarbon chain in high yields (homologation).
The Horner reaction also provides the possibility to prepare carboxylic acids homologized by one carbon atom via the shortest route starting from phosphinoyl compounds functionalized at the α-position with two heteroatoms, namely, phosphorylated formaldehyde acetals and structurally related compounds [132,141]. In this case, carbanions 230 of phosphorylated formaldehyde acetals and structurally related compounds 13-16, 18-32 behave as a masked form of triply functionalized carbanions 231 that may be considered as a synthetic equivalent or carrier of reversed-polarity formate carbanion [O=C-OH] − 232 [20,141]  Carbanions 230, prepared by the deprotonation of the initial phosphoryl compound, react with carbonyl compounds to afford β-phosphorylated alcohols 233, which can be isolated. The subsequent treatment of alcohols 233 with strong bases, usually potassium tert-butoxide, leads to ketene acetals and structurally related compounds 234 that are valuable precursors in the synthesis of organic compounds of different kinds [23,24,132,133,143]. Further acid hydrolysis of compounds 234 produces carboxylic acids 235 (Scheme 71) or their derivatives, for example esters 236, or thioesters 237, depending on the conditions. Scheme 71. Syntheses of carboxylic acids 235 by means of Horner's reaction, R',R'' = H, Alk, Ar.
However, the simplest and most available phosphorylated formaldehyde acetals, dialkyl (dialkoxymethyl)phosphonates 33, do not form stable carbanions [23,132], therefore the attempted synthesis of carboxylic acids and their derivatives by Horner reaction failed for a long time. Among acetals of phosphonate type compounds, only diethyl (5,6-dichloro-1,3-benzodioxomethyl)phosphonate (91) participated in the reaction with ketones at 90 °C in dioxane in the presence of sodium hydride NaH to give ketene acetals in 19%-32% yields [23]. See also Section 3.3 "Alkylation of formacetal carbon atom".
Therefore, the search for efficient precursors for the synthesis of carboxylic acids 235 from carbonyl compounds by the Horner reaction has continued. From the mid-1970s to the early 1980s, many acetal-like derivatives of diethyl formylphosphonates 13-32 [18,19,, where the negative charge of the carbanion was stabilized by two heteroatoms of the "acetal" group, were obtained [54]. See also Figure 2, where R = OEt. In the case of X = Me 3 Si, Peterson olefination prevails over the Horner reaction [54][55][56]110] and trimethylsyloxy fragment is a leaving group.
Because the majority of compounds 18-32 have no substantial advantages over the phosphorylated formaldehyde thioacetals 14, the study of Horner reaction with their participation was confined mainly to academic interest. More detailed studies of reactivity of the majority of these compounds were not conducted. Compound 153 proposed in 1982 [24] reacts like dialkyl (dialkylthiomethyl)phosphonates 107 with aldehydes, in 50%-69% yields, and acetophenone as ketone example, in 24% yield [24,132]. The products of Horner reaction in this case are cyanoenamines 257, whose acid hydrolysis produces linear carboxylic acids 238 homologous to the initial carbonyl compounds [24,25,132]  Like phosphorylated enamines 236 (Scheme 73), compound 257 contains an anion-stabilizing CN-group in the α-position. Resulting cyanoaminoallyl anions 258 combine with alkyl halides to form carboxylic acids 240 through cyanoenamines 259, while the reaction with aldehydes leads to γ-hydroxy acids that undergo cyclization to give β,γ-disubstituted γ-butyrolactones 243 through cyano aminoallylalcohols 260 [24,25,132,144]  It was shown that compound 153 can react also with cyclic semiacetal 262, which was used in one of the stages of synthesis of prostaglandin analog cloprosterol PGF 2 [155,156] (Scheme 85, compound 263).

Alkyl (dialkoxymethyl)phosphinates-H-Phosphinates 34. Syntheses and Chemical Properties
The synthesis of alkyl (dialkoxymethyl)phosphinates-H-phosphinates 34 in yields up to 96% by the reaction of hypophosphorous acid (319) with orthoformates 54 in the presence of catalytic amounts amounts of p-toluenesulfonic acid (p-TolSO 3 H) [57,175]  The chemical properties of phosphinates 34 were studied almost exclusively by the example of ethyl (diethoxymethyl)phosphinate (86). Ethyl (diethoxymethyl)phosphinate (86) retains properties typical for both phosphorus esters and hydrophosphoryl compounds and retains the general ability of phosphorylated formaldehyde acetals to undergo the cleavage of the phosphorus-carbon bond.
Phosphinate 86 is readily alkylated under the action of alkyl halides in the presence of bases: Na, NaH, BuLi (B − ) (via anion 320) to give ethyl alkyl(diethoxymethyl)phosphinates 321 [58,176]  Compound 86 also readily undergoes addition to activated double bonds, or it can transform into three-coordinated phosphorus compounds [59,176,177] It also undergoes Todd-Atherton reaction with phenols and cross-coupling reactions with aryl bromides [106] in the presence of tetrakis(triphenylphosphine)palladium(0), Pd(Ph 3 P) 4 , see Scheme 17. In 86, one of two P-H bonds of initial hypophosphorous acid 319 is protected by a diethoxymethyl group and can be restored in subsequent stages after deprotection [58,176]. When treated with two equivalents of organomagnesium or organolithium compounds, phosphinate 86 produces secondary phosphine oxides 324 [178], a hidden form of unstable primary phosphine oxides 325 apt to disproportionation [179], that can be easily obtained by subsequent acid hydrolysis. Further alkylation of secondary phosphine oxides 324 in the presence of a base leads to unsymmetrical tertiary phosphine oxides 326, which in turn are the hidden form of unsymmetrical secondary phosphine oxides 328. Similarly to primary phosphine oxides 325, compounds 327 can be also obtained by subsequent acid hydrolysis of tertiary phosphine oxides 326. Further oxidation leads to the corresponding phosphonic 328 and unsymmetrical phosphinic acids 329. Unsymmetrical tertiary phosphine oxides 330 can be obtained by the following alkylation of secondary phosphine oxides 327 (Scheme 113). Phosphonic and unsymmetrical phosphinic acids 328 and 329 can also be obtained by the scheme that begins with the alkylation reaction by introducing 86 in the reaction of one or sequentially both P-H bonds, thus solving the problem of selectivity [58,59,176,178], over phosphinates 331 and H-phosphinic acids 332, respectively. The scheme allows one to avoid the use of highly toxic hypophosphorous acid in the syntheses [177]  Due to the unique combination of chemical properties, phosphinate 86 is used in modern organic synthesis and synthesis of biologically active compounds. H-phosphinic analogs of natural α-amino acids 333 were obtained with >95% enantiomeric excess by the reaction of 86 with chiral (S)-N-tert-butylsulfinylketimines (334) [180] (Scheme 115).  3-Amino-2-fluoropropyl-H-phosphinic acid (335), a γ-aminobutyric acid (GABA) analog, a potential pharmaceutical for the treatment of central nervous system diseases, was prepared from compound 323 as the silylated form of ethyl (diethoxymethyl)phosphinate 86 [181]

Phosphorylated Formaldehyde Hydrates-Geminal Diols 35. Syntheses and Chemical Properties
The chemistry of phosphorylated formaldehyde hydrates 35 began to develop since the mid 1990s when diethyl (dihydroxymethyl)phosphonate (337) was obtained in quantitative yield by the reaction of diethyl (diazomethyl)phosphonate (338) with 3,3-dimethyldioxirane-acetone peroxide at 20 °C [60,61] (Scheme 118). The chemical properties of phosphonate 337 provide the possibility of considering it as a hidden form of phosphorylated formaldehyde. Compound 337 reacts with secondary amines R' 2 NH with the cleavage of the phosphorus-carbon bond and formation of the corresponding N,N-disubstituted formamides and diethyl phosphite (6) [60,61] (it behaves as a source of formyl group [C(O)H] + cation, synthon type a 1 [183,184].

Conclusions
Phosphorylated formaldehyde derivatives, i.e., acetals and related compounds, are a group of largely underinvestigated species. The experimental data accumulated since the early 1960s confirm that these compounds can be used in a wide variety of syntheses that have not been fully realized to date. For this reason, the growth of interest to these compounds will allow investigating their chemical properties in more detail and potentially enrich organic and organoelement chemistry with new synthetic methods.