Rearrangements 1,2 -phosphonate-phosphate rearrangement

Acylphosphonates generate acyl anion equivalents with cyanide via phosphonate-phosphate rearrangement. These anions react with aldehydes to provide cross-benzoin... 

The formation of phosphates 90 can be explained by phosphonate-phosphate rearrangement catalyzed by bases [84], The authors of [82] were able to show that phosphonates 89 react with isatin (in the presence of sodium alkoxide), leading to compounds 90. 

The procedure of isotope effect studies will be illustrated on several examples. First one concerns studies of phosphonate-phosphate rearrangement (Scheme 1). Phosphite 3 reacts in the presence of triethylamine with o-nitrobenzaldehyde (Pudovik reaction) to form 1-hydroxyphosphonate 4 as mixture of two diastereo-isomers, 1 1. Amine also catalyses the reverse refro-phospho-aldol (retro-Abramov) reaction of 1-hydroxyphosphonate to phosphite and aldehyde and rearrangement to phosphate 5. In acetonitrile at 65°C Pudovik reaction is much faster than of retro-Abramov reaction and phosphonate-phosphate rearrangement, which rates are comparable. Important fact for the mechanism elucidation was experimental evidence that rearrangement occurs with retention of configuration at phosphorus atom.49... 

Because the phosphonate-phosphate rearrangement requires P-C bond breakage and formation of the P-O bond kinetic isotope studies by means of 13C NMR were chosen.50 13C KIEs were derived from NMR analysis of substrate-o-nitro-benzaldehyde or product-phosphate. Samples of aldehyde were prepared using the dead-end method. To the solution of phosphite 3 and triethylamine in acetonitrile an excess of aldehyde was added and solution was heated at 65°C to complete conversion of phosphonate 4 to phosphate 5 monitored by 31P NMR. The aldehyde conversions 0.2-0.8 were calculated from the balance of concentrations. The changes of 13C composition were determined for carbonyl carbon atom using signal of meta aryl carbon as an internal standard. KIE 1.0223(14) was calculated from the slope of linear relationship of isotopic ratio R and fraction of reaction,... 

Simultaneous electrical conductivity-DTA was used by Romanov et al. (67) to study the thermal behavior of a-oxyalkylphosphonates. It was found that the thermal transformations of these compounds and their analogs are preceded by the ionization of the hydroxy group near the a-carbon atom. On the phosphonate-phosphate rearrangement of a-oxyalkylphosphonates containing electron-donor substituents near the a-carbon atom, no prior decomposition to the initial components takes place, and rearrangement proceeds by an intramolecular tricenter mechanism. 

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]. 

Chemical transformations of a-hydroxyphosphonates Phosphonate-phosphate rearrangement. Dialkyl alkylphosphonates are, in general, more reactive than the corresponding phosphate esters because the carbon has no unpaired electrons to contribute to allow a pn-dm contribution to the P-C bond. This makes the phosphorus atom of phosphonates more electrophilic than the phosphorus atom of the corresponding phosphate ester. The P-C bond is usually stable to hydrolitic procedures. However, a-hydroxyalkylphosphonates, in the presence of alkali, rearrange to give phosphate with cleavage of the P-C bond [220]. 

The phosphate carbanion I obtained as a result of phosphonate-phosphate rearrangement reacts further with a second molecule of aldehyde, forming 1,2-diphenyloxirane (stilbenic oxide) II. The latter undergoes the Homer-Emons reaction to furnish trani-stilbene III. 

Sodium diethyl phosphite reacts with fluorinated alkylketones at temperatures in the -10 °C to 0 °C range, yielding substituted fluoroalkenyl phosphates via phosphonate-phosphate rearrangement of the initially formed P-carbonyl phosphonates [381]. 

Dialkyl (l-hydroxy-2-alkynyl)phosphonates [e.g. (64)], prepared by addition of lithium acetylides to acyl phosphonates, can be converted regioselectively into allenic phosphates via the phosphonate-phosphate rearrangement (e.g. Scheme 104). If sodium alkoxides in alcohols are used to effect the rearrangement, mixtures of allenic and acetylenic products are formed however, use of sodium bis(trimethylsilyl)amide in DMSO furnishes allenic phosphates almost exclusively. 

A DFT study of the origins of stereoselectivity in the aldol reaction of bicyclic amino ketones (20) with aromatic aldehydes has been reported (Scheme 18). ° Base-catalysed direct aldolization of a-alkyl-a-hydroxy trialkyl phosphonoacetates with aldehydes proceeds via a fully substituted glycolate enolate intermediate formed by a [l,2]-phosphonate-phosphate rearrangement. High enantioselectivity can be achieved by the application of chiral iminophosphorane catalysts. 

Another example is the electrocatalytic reaction between aromatic carbonyl compounds and dialkyl phosphonates. Here, rearrangement of the product anion leads to a phosphate as the product [136]. 

A mechanism, via a 6-hydroxy phosphorothiolate 8-mercapto-phosphate rearrangement, will be shown, and these new synthons will be compared with the phosphonate analogs (Wittig -Horner reagent). 

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. 

When the preparation of alkali metal enolates derived from alkanoylphosphonates was attempted by treatment with strong anhydrous bases such as lithium diisopropylamide or sodium hydride, the formation of phosphate phosphonate-type products was observed. This was interpreted in terms of fragmentation of the enolate formed in the first step to ketene and dialkyl phosphite anion (equation 75), and addition of the latter to the carbonyl group of an unreacted acylphosphonate molecules to form a bisphosphonate. Such molecules are known to rearrange to phosphate phosphonates ... 

Yet another rearrangement involving phosphate esters is that of oxiranyl phosphates following their formation by oxidation of enol phosphates (134) by peroxy acids or dimethyidioxiran the products are (2-oxoalkyl)phosphonic diesters (135). A preliminary communication concerning the reaction sequence was included in last year s... 

The mesylate 180, the synthesis of which from the tertiary alcohol required the preparation of the sulfinate followed by oxidation, gave 181 on treatment with TBAF, by an unusual phosphonate-to-phosphate rearrangement of unknown mechanism. ... 

Dinucleoside-a-hydroxybenzylphosphonates 2 in up to 90% yield were synthesized by reacting the symmetric dinucleoside H-phosphonates 1 with benzaldehyde derivative in the presence of catalytic amounts of a tertiary base like diisopropylethylamine (DIPEA), or tri-ethylamine (TEA). Dinucleoside-a-hydroxybenzylphosphonates 2 are consideied uncharged prodrugs of 5 -nucleoside H-phosphonates 3 and 5 -nucleoside monophosphates 4. These two compounds are released by controlled hydrolysis via two different pathways the phospho-nate-phosphate rearrangement and the direct cleavage mechanism [188]. 

A phosphate-phosphonate rearrangement process has also been explored in which a strong base is used to abstract a proton from the position adjacent to an aryl phosphate ester linkage. The product, an or f/io-phosphonopheno I, is generated in excellent yield (Figure 6.16).70 Further exploration of the variability of structure for this type of reaction seems desirable. 

Orthophosphoric and benzylphosphonic acids have been selectively alkylated with triethyl phosphite in a new synthesis of mono-, di-, and triethyl phosphates and of mono- and di-methyl phosphonates.62 A-Methylol carboxamides and sulphonamides react with trialkyl phosphites to give the phosphonate derivatives (78) and (80), respectively.63 However, the mechanism appears to be quite different in each case while the carboamides react by a transesterification-rearrange-ment pathway, the sulphonamides undergo elimination-addition via the imine (79). 

A comparison has been made" of various monoterpenoid rearrangements cataiysed by either zirconium phosphates or by zirconium organo-substituted phosphonates, and acid-catalysed rearrangements of a-trans- and /3-cis-3,4-epoxycaranes have been described." It has been observed" that on exposure to Li (OBu )3AlH, perhydro-naphthalene-l,4-diol monosulfonate ester (269) rearranges to the 11-oxatricyclo-[5.3.1.0.2,6]undecane derivative (270) (see Scheme 88). 

Phosphate-derived a-oxycarbanions can rearrange into a-hydroxy phosphonates. This class of rearrangement is known to proceed with retention of configuration at the carban-ion terminus. The enantioselective version of this rearrangement has been developed using a chiral lithium amide as a base (equation 115) . The reaction of benzyl dimethyl phosphate 182 with amide R,R)-63 in THF gave the hydroxy phosphonate (5 )-183 in 30% in enantioenriched form (52% ee). 

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