Hydrogen phosphonate method

We found that the toxicity and myotic activity of di-isopropyl phosphorofluoridate (XI) were far greater than that of di- propyl phosphorofluoridate. In Report no. 6 on fluoro-phosphonates to the Ministry of Supply3 we described the preparation of di aec.-butyl phosphorofluoridate (XII) by the hydrogen phosphite method (p. 6). The compound was found to be very toxic and to produce severe myosis in man and animals. The symptoms displayed during and after exposure were identical with those produced by di-isopropyl phosphorofluoridate. The L.c. 50 for di-sec.-butyl phosphorofluoridate for mice for deaths within 2 hr. was 0-6 mg./l., and that for deaths within 48 hr. was 0-54 mg./l. 

Improved yields of epoxyphosphonates of type (48) are reported for a development of existing synthetic methods, involving mixing of stoicheiometric amounts of hydrogen phosphonate, a-halogeno-ketone, and alkoxide.42... 

Addition methods -The addition of dialkyl hydrogen phosphonates to compounds... 

The phospho-aldol reaction has been known for many years within the phosphorus-chemistry community, under many names (including the Abramov and Pudovik reactions) and is one of the most valuable and powerful synthetic processes for the construction of phosphorus-carbon bonds [1]. The reaction, illustrated in its usual form, is outlined in Scheme 1 a. It involves an addition reaction between a hydrogen-phosphonate ester and a carbonyl substrate to afford an alpha-(a)-functionalised phosphonate ester. Whilst alternative methods or activation have been explored [2], the phospho-aldol reaction is most commonly performed under conditions of base catalysis [3]. 

Considerable work has been published on stoichiometric asymmetric routes to a-functionalised phosphonate esters. One of the most commonly exploited methods is the phosphonylation of a chiral aldehyde or imine by a phospho-rus(ni) ester (Scheme lb) or a by a hydrogen phosphonate (Scheme la). Thus, a team from Bristol-Myers Squibb reported the base-mediated addition of dimethyl H-phosphonate (DMHP) to a chiral aldehyde (Scheme 2) as a key step in their synthesis of renin inhibitors [6j. Subsequently, work from the Hoechst AG laboratories in Frankfurt used a related approach to the building of HIV protease inhibitor frameworks (Scheme 3) [9]. 

This implies that these compounds have P-H type acidity and are therefore considerably less acidic than the corresponding P-OH type acids. It was established by means of P NMR spectroscopy that in dimethoxy ethane, the acidity of dibutyl hydrogen phosphonate is close to that of ethanol, and that these P-H acids are stronger than the corresponding N-H acids [3]. The pK values of a series of H-phosphonate diesters have been calculated by the so-called premetallization method [4], according to the following equation ... 

Transesterification of a Phosphonate with a Diol. This method proceeds well in the case of 0,0-dialkyl hydrogen phosphonates (101) but less selectively with 0,0-dialkyl alkyl- or arylphosphonates. With 0,0-diaryl alkylphosphonates, ester exchange is an effective route to pol5uneric phosphonates (102-104) ... 

The most reliable method for characterization of the product H-phosphonate IS H and P NMR. Hydrogen-phosphonates have a characteristic coupling constant of the P-H (Jp.n = 600-605 Hz) that can be seen in tire H-NMR spectrum as well as in the H-coupled P NMR spectrum. Furthermore, the P NMR spectrum of a nucleoside 3 -H-phos-phonate is split into another doublet due to the C-3 hydrogen (Jp.n = 8-12 Hz). 

Foley, P.J., Jr. 1969. A novel method of converting aldehydes into nitriles under mild conditions. The reaction of diaUcyl hydrogen phosphonates with oximes. J Org Chem... 

List was the first to explore this possibility, examining the Hantzsch ester mediated reduction of a,P-unsaturated aldehydes [209], Using 20 mol% of the binaphthyl derived phosphonate salt of morpholine (153) in dioxane at 50 °C, a series of P-aryl a,P-unsaturated aldehydes underwent transfer hydrogenation with Hantzsch ester 154 with excellent levels of absolute stereocontrol (96-98% ee) (Scheme 63). The method was also applied to the aliphatic substrates ( )-citral and famesal to give the mono-reduced products in 90% and 92% ee, respectively. Significantly, in line with many of the chiral secondary amine catalysed transformations described above the reactions follow a simple and practical procedure without the need for exclusion of moisture and air. 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

In addition to the conversion into phosphonochloridates as described in Section 10.10.2.1.2, phosphonate monoacids can also be activated for coupling via some of the popular reagents from standard peptide chemistry, such as BroP, 77 BOP/ and PyBOP. 79 One-pot activation and coupling of hydrogen phosphinates with a-hydroxy acids is also possible via the method outlined in Section 10.10.2.1.3. 76 The procedure outlined in Scheme 19 illustrates an optimized procedure for coupling a hindered phosphonate 57 and an a-hydroxy acid derivative via the phosphonochloridate 72 ... 

Because of the possibility of racemization during the transesterification reaction (strong basic conditions) alternative methods are reported. These include transesterification in the presence of the KF/18-crown-6 ether 461 or the use of titanium tetraalkoxides. 471 The methods are efficient and represent a route to any required dialkyl ester using diphenyl esters as starting materials. Diphenyl groups can also be removed by hydrogenation in the presence of platinum dioxide (Adams catalyst) to provide the free phosphonic acid moiety directly)46 ... 

The main problem here is removing the phenyl ester groups from the phosphonic moiety.We have found that convenient routes for deblocking are hydrogenation on Adams catalyst and transesterification methods followed by hydrogen bromide in glacial acetic acid treatment. The best results ewre obtained if transesterification was carried out using potassium fluoride-crown ether-methanol system. 

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