Hydroxyalkylphosphonate

By reaction of PC13 with aldehyde or ketone in the presence of acetic acid followed by hydrolysis, a-hydroxyalkylphosphonic acids are obtained, according to Eqs. (57)-(59). 

Neutral esters of the a-hydroxyalkylphosphonic acid are formed when PC13 is substituted by dimethoxychlorophosphine see Eqs. (60) and (61). 

By substituting n-butyldichlorophosphine for PC13 the butyl monoester of the a-hydroxyalkylphosphonic acid is formed. If there are 12 or more carbon atoms in the molecule the compound will be surface-active and still soluble in water. Alkali salts of the free phosphonic acids obtained by the reactions... 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

A study of the kinetics and products of the thermolysis of a series of diaryl-phosphinic azides has been reported.119 Diethyl 1-diazomethylphosphonates undergo an aldol-type reaction with aldehydes to give l-diazo-2-hydroxyalkylphosphonates (152).120 Acidification of the diazophosphonates (153) possessing a chiral phosphorus centre yields mixtures of diastereoisomers (154) and epimers at C. For given R1 and R2, the reaction becomes increasingly stereoselective for X= OAc < Cl < OTs. It may be argued that protonation of (153) will yield a mixture of diastereoisomeric di-... 

Further studies on 1,3-dipolar addition reactions of diazophosphonates have been recorded,122 and work on 2-diazo-l-hydroxyalkylphosphonates also continues.123 The ester (155 R = H) reacts with esters of acetylenedicarboxylic acid without liberation of nitrogen to give stereoisomeric C-phosphorylated pyrazolines, which can be decomposed with both phosphorus-carbon and carbon-carbon bond fission, affording mixtures containing dimethyl acetylphosphonate, dimethyl hydrogen phosphonate, and tri(alkoxycarbonyl)pyrazolines. In the reaction between the same diazophosphonate and diazomethane, the latter conceivably acts as a basic catalyst for proton transfer in a series of steps which includes phosphonate-phosphate isomerization. The importance of a labile proton is demonstrated by the fact that the ester (155 R = Me) does not react in the manner described above. 

The condensation of aldehydes and ketones with aminoacetonitriles, although it requires more vigorous soliddiquid catalytic conditions to produce the cyano-enamines, is preferable in many respects to the traditional Wittig-Horner or Peterson procedures [45]. Hydroxyalkylphosphonates are obtained from the catalysed aldol condensation of nitromethane with acylphosphonates [46]. 

A facile procedure for highly regioselective and efficient synthesis of cx-hydroxyphosphonates (274) and (275) based on the reaction of trialkyl phosphites with epoxides in LiC104/Et20 has been presented (Scheme 70). p-Hydroxyalkylphosphonates (276) have been prepared under neutral conditions by reaction of diethyl iodomethylphosphonates (277) and carbonyl... 

Methods involving electrophilic fluorination have been used to prepare a number of fluorophosphonates. Examples include benzylic a,a-difluoromethyl-phosphonates, e.g. 157, by the reaction of the carbanion of 156 with N-fluorobenzenesulfonimide (NFBS) (Scheme 10), which is claimed to be superior to DAST, and (a,a-difluoroprop-2-ynyl)phosphonates 159 by the direct di-fluorination of the a-ketophosphonate 158 (Scheme ll). Compound 158 is prepared by Pfitzner-Moffatt oxidation of the corresponding alcohol and it is worth noting that few such oxidations of a-hydroxyalkylphosphonates have been reported. 

Hydroxyalkyt and Epoxyalky Acids. The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates ° and magnesium oxide has been reported to be an effective catalyst for the reaction. The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a, -dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the jyn-isomer 171, and the statin analogue 2-amino-1-hydroxy-3-phenylpropylphosphonic acid (173) (Scheme 15). Catalytic asymmetric... 

Hydroxyalkylphosphonates have been prepared by reduction of the corresponding ketones. These include phosphonomalate esters by highly diastereose-lective reduction of 3-phosphonopyruvates with NHs.BHa and both 2-hydroxyalkyl-phosphonates, e.g. 178, and thiophosphonates by asymmetric hydrogenation using chiral ruthenium catalysts. An enantioselective synthesis, from 179, of both enantiomers of phosphonothrixin 180 and their absolute stereochemistry have been reported.The epoxide 179 was prepared from 2-methy -3-hydroxymethyl-1,3-butadiene via a Sharpless epoxidation. 

Nagase, T., Kawashima, T., and Inamoto, N., A new synthetic route of P-hydroxyalkylphosphonates from P,Y-epoxyalkylphosphonates, Chem. Lett., 1997, 1984. 

The catalytic enantioselective reduction of 1-ketophosphonates has recently been developed. This approach takes advantage of a development in the enantioselective reduction of prochiral ketones to chiral alcohols by means of catalytic amounts of oxazaborolidines with borane as reducing agent. Thus, the enantioselective reduction of 1-ketophosphonates is accomplished by treatment with different boranes, BH. THF (0.9 eq), BII3Me2S (0.66 eq),5 545 qj- catccholborane (1.1 eq)5° 5 6 in different solvent systems in the presence of a catalytic amount of freshly prepared B-n-butyloxazaborolidine, (5) or (R) (Scheme 7.93). The reaction is complete in about 5 h and produces the expected dialkyl 1-hydroxyalkylphosphonates in satisfactory yields (53-98%). 

A clear illustration of the advantages of this synthetic procedure is provided by the conversion of optically active dialkyl 1-hydroxyalkylphosphonates into dialkyl 1-aminoalkylphosphonates by the Mitsunobu azidation. For example, a sequence of reactions for the conversion of optically active diethyl 1-hydroxyalkylphosphonates into diethyl 1-aminoalkylphosphonates proceeding in 50-88% overall yields and 48-82% ee s has been developed (Scheme 7.94).- ... 

Meier, C., Laux, W.H.G., and Bats. J.W.. Asymmetric synthesis of chiral, nonracemic dialkyl a-hydroxyarylmethyl- and a-, P-. and y-hydroxyalkylphosphonates from keto phosphonates, Liebigs Arm., 1963, 1995. 

Okamoto, Y, and Sakurai, H., Synthesis of fatty aldehyde through the intermediate of diethyl a-hydroxyalkylphosphonate, Kogyo Kagaku Zasshi, 70, 797, 1967 Chem. Abstr, 68, 48979, 1968. 

Besides the intramolecular cyclization of co-haloalkyl-substituted compounds, a variety of five- and six-membered 2-oxo-1,2-oxaphosphacyclanes can be obtained via thermal cyclization of co-hydroxyalkylphosphonates (preformed or obtained in situ) and related compounds [66-73], As the reaction proceeds through intramolecular transesterification requiring a prolonged heating, use of bases such as lithium hydride, sodium hydride, sodium alcoholate, etc. accelerates the reaction and increases the yield of heterocycles 62 (Scheme 35) [54],... 

If the starting co-hydroxyalkylphosphonate is obtained via the Abramov reaction, presenting a convenient route to a-hydroxyalkylphosphonates, the final heterocycles formed in the one-pot process may possess additional functionality such as a hydroxy (compound 70, Scheme 39) [85] or phosphoryl group (compound 71, Scheme 40) [86], In the latter case, the starting carbonyl compounds of rather complex structure gave rise to directional synthesis of biologically active compounds 72 and 73. 

The reactions of dialkyl phosphonates and secondary phosphine oxides with aldehydes have been used to prepare ct-hydroxyalkylphosphonates and various a-functionalized tertiary phosphine oxides. In contrast to previous reports, dialkyl phosphonates have been shown to react exothermically with benzophenone in the presence of base to give... 

It has been shown that the rearrangement of a-hydroxyalkylphosphonic acid diesters to phosphates is subject to general base catalysis and a transition state similar to (95) was proposed. Hydrolysis of the aroyl-phosphonate esters (96) in aqueous dioxan with phosphate buffer is also... 

In Section VILA, the 1,2-addition of a hydrogenphosphonic diester or related compound to an a,j5-unsaturated aldehyde or analogous ketone " " was discussed in relation to the synthesis of (l-hydroxyalkyl)phosphonic diesters. The latter are formed under condition of kinetic control whereas 1,4-addition (the so-called Pudovik reaction), which leads to the (2-oxoalkyl)phosphonic diester occur under thermodynamic controP" ". In general, reactions which involve ethylenic aldehydes, or acetylenic aldehydes or ketones, tend to result in adduct formation across the carbonyl group, whilst ethylenic ketones tend to take part in 1,4-additions and afford 3-oxoalkyl phosphonic (or phosphinic) acid systems 550 34,946-949 consistent with Markovnikov predictions. Such statements are a broad oversimplification, however, at least with regard to the formation of the oxoalkyl phosphonates. In practice, the manner of addition depends on experimental circumstances, the nature and even amount of catalyst and other factors For instance, for the additions of dimethyl hydrogenphosphonate to the ketones 561 ( = 1 or 2) and 559 (R" = H, R = 2-furyl, R = Me), carried out by the addition of a trace of saturated MeONa-MeOH solution to a mixture of reactants in diethyl ether, yielded (within 5 min) the respective 1,2-adducts (1-hydroxyalkylphosphonates) in yields of64,69 and 52% ... 

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