Phosphonylation

It is difficult to introduce phosphorus into a linear polymer by conventional polymerisation or co-polymerisation of phosphorus containing monomers. The polymers containing 

A diamide of methylphosphonic acid [MeP(0)(NBu2)2, a phosphono-amidate] has been shown to lose the methyl group and substitute into indole (80JGU618) there are no other reports of this reaction. 

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Electrophilic reaction can account for the additions of morpholine or phosphonyl (Scheme 14), or... 

Pentavalent phosphorus derivatives can be converted to phosphonyl halides or phosphine oxides by partial hydrolysis or by other oxygen donors. 

CLAY - KINNEAR - PERREN Phosphonyl Chloride Synthesis Synthesis ol alkyl phosphonyl chlorides Irom alkyl chlorides or from ethers with PCI3 AICI3... 

MICHAELIS BECKER NYLEN Phosphonylation Nucleophilic attack oi lithium dialkylphosphonates on pyndkim sells to produce pyridine phosphates... 

A general synthesis of phosphonyl thiadiazoles has been recently disclosed starting from the hydrazone 55. The hydrazones were prepared from acyl phosphonates, which in turn were made from acid chlorides 54. Thus treatment of the hydrazone 55 with thionyl chloride in the presence of DMF and sodium chloride provided the thiadiazoles in... 

An alternative approach is to have the chiral auxiliary on the enolate. Sweeney has reported the addition of bromoacyl sultam 102 to phosphonyl imines 103, which afforded the cis- or trans-aziridines with high levels of diastereoselectivity depending on the imine substituent (Scheme 1.30) [55]. 

Sulfonylaziridine 243 was halogenated in carbon tetrahalides in the presence of KOH as base [86] (Scheme 5.61). Although other examples of electrophile trapping of sulfonyl- and phosphonyl-stabilized metalated aziridines exist, the reactions were not stereoselective [87]. 

Recently, Fossum et al. prepared several phosphine-oxide-containing monomers (Scheme 6.23).163 These monomers were used to prepare hyperbranched polymers in a typical aromatic nucleophilic substitution. However, only oligomers with M lower than 2500 g/mol were obtained. These results did not surprise us, since our previous work demonstrated that the para-hydroxyl group of the phosphonyl group is not very reactive and would require higher reaction temperatures.11... 

Figure 10.28 Complementary routes for the stereoselective synthesis of hydrolytically stable sugar phosphonates, either from the bioisosteric phosphonate analog of DHAP or from phosphonylated aldehydes.

Helquist s work on the use of diazomalonate in the synthesis of oxazoles has been extended to other diazocarbonyl compounds in our own laboratory.<92TL7769, 94T3761> Thus it was found that sulfonyl-, phosphonyl- and cyano-substituted diazoesters gave the corresponding 4-functionalised oxazoles 30 in acceptable yield (Scheme 20). In many cases the yield of oxazole was significantly improved by the use of rhodium(II) trifluoroacetamide as catalyst. The 4-cyano-oxazole 30 (R = Me, Z = CN) proved interesting in that it allowed the formation of a bis-oxazole 31 by a second rhodium catalysed reaction (Scheme 20). 

Various cyclic phosphonate esters 36 and 37 have been described previously as products from the HHT reaction of 25 with the appropriate cyclic phosphite. A complementary method has also been developed from the V-protected phosphonyl chloride 84, which was readily prepared from the corresponding phosphonic acid 83. Subsequent reaction of 84 with the appropriate diol produced the cyclic phosphonate esters 85 (63). Higher homologs of 85 have also been prepared from the analogous propane or butane diols. 

Thiazolines (57) can be phosphonylated in a stereospecific maimer by diastereomerically pure phosphites (58) to give 4-thiazohdinylphosphonates (59) via a Pudovik reaction <96SC1903>. 

The prototype member of the ANPs is (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine (HPMPA) (Fig. 2), first described for its broad-spectrum anti-DNA virus activity in 1986 (De Clercq et al. 1986). Then followed by the description of various other acyclic nucleoside phosphonates in 1987 (De Clercq et al. 1987). At present three acyclic nucleoside phosphonates have been licensed for clinical use cidofovir, adefovir, and tenofovir (Fig. 2). 

This chapter surveys the literature published from 1995 to 2003, concerning the reactivity and the chemical applications of the four main families of phosphorus centered radicals, i.e., phosphinyl (L2P )> phosphonyl (L2P =0), phospho-niumyl (L3P ) and related charged species, and phosphoranyl (L4P ) radicals. Due to their specificity, a section is devoted to the generation and properties of persistent and stable phosphorus centered radicals. 

Although their chemistry is less developed than that of phosphonyl, phospho-niumyl or phosphoranyl radicals, many structural studies have been devoted to phosphinyl radicals [1]. Like their nitrogen analogs,phosphinyl radicals are 7i-type radicals (Fig. 1) and because of the very small s character of their SOMO, the magnitude of their phosphorus hyperfine coupling constants flp is below 15 mT [1]. 

The characteristics of a large number of phosphonyl radicals [L2P(0)] have been extensively listed over the last three decades [1]. Phosphonyl radicals are a radicals [7] (Fig. 2) and due to the significant s-character of their SOMO they exhibit phosphorus hyperfine coupling constants ap ranging from 30 mT to 70 mT [1]. 

The reactivity of electrochemically generated phosphonyl radicals has been recently reviewed by Kargin and Budnikova [8] and will not be considered here. The reactivity of phosphonyl radicals is mainly accounted for by the three processes [9] shown in Scheme 2 radical addition (1), atom transfer (2 and 3), and electron transfer (4). 

Scheme 3 Radical chain reaction involving phosphonyl radicals...

R2P(0)H) and phosphonates (R02P(0)H) as hydrogen atom donors and the corresponding phosphonyl radicals as chain carriers (Scheme 3). 

The reactivity shown in Scheme 3 results from the low bond dissociation energy (BDE) of the P-H bond [11] k=l.2 10 M s for the H-transfer from R02P(0)H to a primary C-centered radical) and the fast halogen-atom transfer from a C-halogen bond to a phosphonyl radical [9,12] (fc=4 10 M s for f-Bu-Br and k=83 10 M s for Cl3C-Br). Piettre et al. [13] pointed out that these chain reactions were even more efficient when dialkylthiophosphites and the corresponding dialkylphosphinothioyl radicals were involved. 

Addition of phosphonyl radicals onto alkenes or alkynes has been known since the sixties [14]. Nevertheless, because of the interest in organic synthesis and in the initiation of free radical polymerizations [15], the modes of generation of phosphonyl radicals [16] and their addition rate constants onto alkenes [9,12,17] has continued to be intensively studied over the last decade. Narasaka et al. [18] and Romakhin et al. [19] showed that phosphonyl radicals, generated either in the presence of manganese salts or anodically, add to alkenes with good yields. 

Murphy et al. showed that EPHP [25] and L2P(0)H [26] can also be used in radical C-C bond forming reactions (Scheme 8). Recently, Piettre et al. [27] used the sodium salt of hypophosphorous acid as H-donor and the subsequent phosphonyl radical as phosphonylating agent for the preparation of 3-fura-nosyl-6 -furanosylphosphinate (Scheme 9). 

Scheme 10 Reductive cyclization involving phosphonyl radicals. Reprinted with permission from [28a]. Copyright 2001 Pergamon Press...

Fluorinated phosphonates exhibit interesting properties as enzyme inhibitors, chelating agents or as fuel cell electrolytes [29] however, only few methods of preparation for these compounds are available. Burton et al. [30] developed several methods to prepare fluorinated phosphates which involve phosphonyl, and likely phosphoranyl radicals as chain carriers (Scheme 11). 

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