A-Hydroxyalkyl phosphonates

The formation of phosphate esters from amine-catalyzed reactions between dialkyl phosphites and ketones often accompanies the expected production of (a-hydroxyalkyl)phosphonic acid esters (see Section 2.1). It is also known that under... 

An alternative route to a hydroxyalkyl phosphonate is by LiBHa reduction of the A-protected ester (285) spontaneous cyclization to the cyclic phosphonate (286) occurs (Equation (19)) <94TL3273>. 

The remarkable ease with which (a-hydroxyalkyl)phosphonic acids and analogous phosphinic acids are produced through a very simple procedure engendered much early interest in these acids, all the more because of the extraordinary ease with which these acids could be returned to their precursors through cleavage at the phosphorus-carbon bond under mild conditions. Less readily available and, as a consequence, less extensively examined, but nevertheless more important from the viewpoint of their potential biochemical... 

Simple derivatives of (a-hydroxyalkyl)phosphonic and analogous acids have been obtained directly by procedures analogous to those adopted for the parent compounds. Thus, O-acetates of (2,2,2-trichloro-l-hydroxyethyl)phosphonic acid esters have been prepared through the interaction of the appropriate halogenated acetaldehyde and phosphorous-acetic acid anhydrides An aromatic aldehyde and dialkyl phospho-roisocyanatidite in the presence of water or an alcohol yields analogous 0-carbamoyl derivatives of (a-hydroxybenzyl)phosphonic diesters, probably through cyclic intermedi-ates ". ... 

Much attention has been devoted to the conversion of aldehydes into the trimethylsilyl ethers of (a-hydroxyalkyl)-phosphonic acids 210 or analogous -phosphinic acids, or of the corresponding (a-hydroxyalkyl)phosphonic diamides 211 by the use of dialkyl trimethylsilyl phosphite or Me3SiOP(NEt2)2 (or other phosphorodiamidite) It is a reaction which occurs very readily, even at room temperature, and the ready methanolytic or hydrolytic removal of the silyl protecting group makes the procedure an attractive alternative to the direct synthesis of the (a-hydroxyalkyl)phosphonic acids from dialkyl hydrogenphosphonates and carbonyl compounds. Silyl-protected hydroxy-phosphonic and -phosphinic acid derivatives are useful for further synthetic development. ... 

Although it has been stated that di- and tri-haloketones and a-haloaldehydes (irrespective of the degree of halogen substitution) tend to yield only enol phosphate esters, further qualification of this statement is appropriate. The formation of silyl ethers from aldehydes or ketones and silyl phosphites has already been noted (see section III.A). Reactions between silyl phosphites and trifluoroacetaldehyde or perfluoroacetone and other similar compounds initially lead to silyl ethers of (a-hydroxyalkyl)phosphonic diesters in which all the fluorine is retained, although subsequent change leads to fluorinated enol phosphate esters. Sekine et also observed the formation of (a-silyloxyalkyl)phospho-... 

Instability in the supposedly stable phosphorus-carbon bond displays itself not only in unfortunate ways, leading as it does to side reactions and the formation, in synthesis, of unwanted by-products, but also in a constructive manner, forming the basis of reaction sequences of outstanding value in synthesis, as for example in alkene-forming reactions. Instability is an inherent property of (a-hydroxyalkyl)phosphonic acids which manifests itself in phosphorus-carbon bond cleavage as a result of the action of heat or of alkali, and which can lead either to dissociation into precursors or to rearrangement to phosphates (a-oxoalkyl)phosphonic derivatives are susceptible to attack by nucleophiles, a process which also results in carbon-phosphorus bond fission. 

The rearrangement of (a-hydroxyalkyl)phosphonate into phosphate ester is not universal (l-hydroxy-2-nitroalkyl)phosphonic esters do not rearrange under the influence of heat whether aided, or not, by added base and the reaction between (Me0)2P(0)H and MeCOCH=CHPh at 130-160 °C yields the 1,2-adduct (105 R = Me) which is stable to base (MeO or EtjN). On the other hand, 105 (R = H) partially decomposes in the presence of MeO and the products include the phosphate 106 together with methyl cinnamate and cinnamyl alcohol, as might be expected from the action of base on cinnamaldehyde Other compounds which undergo base-catalysed rearrangements include 107, the indanones 108 (R = H or the hydroxy phosphinic esters 109 (X = O or S, R =... 

The MBH reactions of diethyl vinylphosphonate dates back to 1990, and they present similar reactivities to alkyl acrylates. It was found that diethyl vinylphosphonate can be coupled with various aliphatic aldehydes in the presence of DABCO to give moderate to high yields of the corresponding a-hydroxyalkyl phosphonates 85. However, this approach was not effective for aqueous formaldehyde and polyoxymethylene, and the corresponding a-hydroxymethyl phosphonates 87 can only be obtained through a Wittig Horner-type reaction from tetraethyl methylenediphosphonate 86 and formaldehyde (30% aq.) in the presence of a weak base K2CO3 (6-8 m) (Scheme 1.42). 

In the absence of a solvent and excess of chloral, the reaction rate for this reaction may be expressed by a third-order equation-second order with respect to dimethyl H-phosphonate and first order with respect to the chloral [177]. In dioxane solution and excess dimethyl H-phosphonate, the dependence of the reaction rate on the chloral concentration is the same. In addition to the chloro-containing a-hydroxyalkyl phosphonate, which is the main product under the above conditions, a side product formed as a result of dehydrochlorination of the main product, followed by phosphonate-phosphate rearrangement, has been also isolated. The presence of a base such as triethylamine, alkali metal alkoxides and hydroxides, or sodium carbonate accelerates the dehydrochlorination process. An example of this side reaction is the transformation of dialkyl-2,2,2-trichloro-l-hydroxyethyl phosphonates into dialkyl-2,2-dichlQrovinyl phosphates in the presence of sodium hydroxide [181,182]. 

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