Anions phosphites/phosphonates

When the substituent becomes very anion-stabilising, as in 42, the ylid may not react with ketones and anions of phosphonate esters are usually preferred in the Homer-Wadsworth-Emmons (HWE) variant.11 The reagent triethyl phosphonoacetate 46 is made by combining a phosphite (EtO)3P instead of a phosphine, with ethyl bromoacetate. Displacement of bromide 44 gives a phosphonium ion that is dealkylated by bromide 45. 

Anomalous Arbuzov reactions have been reported to occur between triethyl phosphite tmd unsaturated A-substituted derivatives of adenine and cytosine (225-231 B = adenin-N -yl or cytosin-N -yl). Thus, both ( ) and (Z) forms of (225) yield the corresponding (226). However, (227) yields the A-ethyl derivatives of the heterocycles, although in the presence of iodide anion the phosphonates (228) can be obtained. The chloroallene (229) yields (230) in the presence of iodide anion an additional product was ( , )-(231). In Michaelis-Becker reactions, (229) affords (231) with or without (230),... 

Because dialkyl phosphonates undergo phosphite-phosphonate tautomerism, a simple strategy to accelerate the phosphite-phosphonate tautomerization is the deprotonation of phosphonates using a base. Inorganic bases, such as potassium carbonate, which have relatively weak basicity and low solubility in organic solvents, could made the dialkyl phosphonate to generate an active phosphite anion at... 

The results presented in this review concern this metal-catalyzed mechanism. Depending on the nature, anionic or neutral, of the different nucleophiles, the result of the arylation can be a neutral substitution product or a cationic one, which most often, in the last case, undergoes an evolution, for example (starting form a phosphite) to a phosphonate or, after deprotonation, to an arylamine or to an arylether (Fig. 2). 

Olefination Reactions Involving Phosphonate Anions. An important complement to the Wittig reaction involves the reaction of phosphonate carbanions with carbonyl compounds 253 The alkylphosphonic acid esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are generated by treating alkylphosphonate esters with a base such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.254... 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

A different approach must be used for the photochemical hydrophosphination of electron-poor olefins, and this involves a PET reaction. Silyl phosphites (e.g., 30) were used as electron donors, whereas conjugated ketones have the double role of electron acceptors and absorbing species. Thus, the irradiation of a mixture containing 2-cydohexenone and 30 generated an ion pair. The phosphoniumyl radical cations decomposed to give trimethylsilyl cations (which in turn were trapped by the enone radical anion) and phosphonyl radicals. A radical-radical combination afforded the 4-phosphonylated ketones in yields ranging from 78% to 92% (Scheme 3.20) [49]. This reaction was exploited for the preparation of substituted phosphonates, which serve as key intermediates in the synthesis of a class of biologically active compounds. 

The arylation of phosphite anions using several iodonium salts is the most important reaction of this Section. Although aryl phosphonates have been prepared by numerous methods, this approach has the advantages of easy availability of starting materials, mild reaction conditions, simple workup, and better yields. 

Phosphonate Arene Osmium(II) Complexes. Benzene osmium(II) phosphonates have been made via the initial reaction of phosphite-containing osmium cations of type 147 with Nal. Demethylation occurs, and the anionic complex 182 is obtained. Protonation with trifluoroacetic afforded adduct 183 which generated complex 184 on treatment with pyridine. The latter was shown to be a precursor of the thallium complex 185 containing the chelating osmium phosphonate 115). 

A system analogous to a cyanohydrin is a siloxyalkylphosphonate. Thus, the diethyl 1-phenyl-1-tri-methylsiloxymethylphosphonate carbanion derived from (61) on treatment with LDA acts as an effective acyl anion equivalent in the preparation of a-hydroxy ketones and ketones. The phosphonate (61) is formed from triethyl phosphite, benzaldehyde and TMS-Cl in excellent yield. 

A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,P-unsaturated esters followed by in situ cyclisation. Other asymmetric syntheses include those of (/ )- and (S)-piper-idin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiazoline. In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used. 

The previous reactions suggest that trialkyl phosphites are able to react with acylphosphonates. Effectively, it has been shown that the reaction of trimethyl phosphite with dimethyl aroylphos-phonates under appropriate conditions leads to the formation of anionic adducts that decompose to give phosphonyl carbenes and trimethyl phosphate. These carbene intermediates can react with further trimethyl phosphite to give ylidic phosphonates, or, when suitable < rt/z<9-substituents are present on the aromatic ring, intramolecular carbene insertion reactions can occur to give cychc systems (Scheme 7.4).38.4o,56,58-65... 

A more convenient and more efficient synthetic procedure has featured the use of protic solvents (alcohol or phenol) on heating. When ethyl acrylate is treated with triethyl phosphite in these conditions, diethyl 2-(ethoxycarbonyl)ethylphosphonate is isolated in fair to good yields (50-90%, Scheme 8.48). The use of protic solvents provides a source of proton for the anionic site of the zwitterionic adduct and a nucleophile for the dealkylation step. However, it has been demonstrated that superior yields of the expected phosphonates are obtained if phenol is used as the proton source-dealkylating agent rather than a simple alcohol.Analogously, the reaction has been performed in the presence of an acid (AcOH, CF3CO2H). 8 5 For example, 2-(methoxycarbonyl)-... 

In the reactions of chloromethyl derivatives of furancarboxylic esters with sodium diethyl phosphite in CgHg at 80°C, the corresponding phosphonates are formed according to the Michaelis-Becker scheme. By contrast, when the bromo derivatives are used, the formation of both phosphonates and reduction products resulting from nucleophilic and halophilic attack by the phosphite anion takes place (Scheme... 

A new synthesis of a)S-unsaturated acids has been developed through alkylation of dibenzyl phosphite anion followed by carboxylation to give the phosphonate (11), which gives the olefin on reaction with aldehydes and two... 

Evidence has been presented which appears to support an earlier hypothesis regarding the reaction between sodium dialkyl phosphites and polyhalogeno - methanes according to this, the phosphite salt and bromotrifluoromethane yield (difluoromethylene)bisphosphonic tetraesters through the abstraction of the bromonium cation by the phosphite anion, and this is followed by phosphorylation of the subsequent carbanion. The present evidence is based on the treatment of diethyl (dichlorofluoromethyl)phosphonate with sodium diethyl... 

Aryl phosphonates. Phosphite anions react with diaryliodonium salts in hot DMF. Arylphosphonate esters are obtained in 79-93% yield. 

A detailed study of reactions between dialkyl phosphite anions and nitrobenzyl bromides has been described. In reactions between the halides and the phosphites (RO)2PONa in a solvent (THF, PriOH, or MeOD) the observed products (Z = 2-, 3-, or 4-nitro), apart from phosphonic diester (104), are those of reduction, (105) or (106), coupling (107), and ether formation (108). Phosphonate formation was moderate for Z = 2-nitro (R = Me), rather higher (51-97% isolated yields) for Z = 3-nitro (R = Me or Pr ), but extremely low for Z = 4-nitro (R = Me) and absent for R = Pr . In all cases when R = Me, ether formation also occurred. In cases where the yields of phosphonate were low, the yields of (107) were correspondingly high, and vice versa. Reactions performed in darkness, daylight or UV, produced little variation in the yields of phosphonate ester (R = Me) for Z = 3-nitro, but for Z = 2-nitro- or 4-nitro-, no diisopropyl phosphonates were obtained under various conditions. Probable mechanisms of reaction were discussed. ... 

Although it might be expected that reactions which employed triarylmethyl halides would occur very readily, such reactions are rendered potentially more complex by the known nature of the halides and their propensity for involvement in free radical reactions. Whereas normal alkylation proceeds between sodium diethyl phosphite and diphenyl-methyl halides, success, or otherwise, in the use of the triphenylmethyl halides depends to some extent on the individual halide and on the metal in the phosphite salt. Thus, in an early study (in 1939), Arbuzov found that in reactions between silver dialkyl phosphites and triphenylmethyl bromide, dialkyl triphenylmethylphosphonates were indeed formed, but the use of the corresponding alkyl chloride provided the phosphite triester instead (metal dialkyl phosphites possess ambident anions ). A later study confirmed the behaviour of the silver salts towards the chloride, but also showed that, whereas dialkyl phophites with primary alkyl groups yielded phosphonic diesters (as had already been found), those with secondary alkyl groups afforded phosphite triesters moreover, the presence and nature of aromatic substituents were also able to control the course of the reaction. Reactions which involve triarylmethyl halides and sodium dialkyl phosphites may well be of a free radical nature since repeated studies have demonstrated the forma-... 

The use of oxirane together with Na2HP03 to prepare (2-hydroxyethyl)phosphonic acid as its disodium salt is of historical interest. Other poorly exploited, yet interesting and potentially valuable, reactions include the combination of a trialkyl phosphite and dialkyl chlorophosphate with an oxirane to yield O-phosphorylated derivatives of (2-hydrox-yalkyl)phosphonic diesters (reaction 10)" and, following the initial reaction of an a,j8-unsaturated ketone with a phosphorus(III) triester to give the cyclic phosphorane 272, the subsequent further reaction of the latter with an aldehyde followed by hydrolysis (reaction 11)" Dialkyl acetyl phosphites are reported to react with oxirane through anionic intermediate species with the formation, albeit in low yields, of dialkyl (2-acetyloxyethyl)phos-phonates hydrolysable with concentrated HCl, to give (2-hydroxyethyl)phosphonic acid ... 

The formation of the dialkyl (2-oxoalkyl)phosphonates (539) illustrates the regioselec-tive nucleophilic attack by phosphite anion, with rearrangement and displacement of sulphinate anion, applicable when R = C1-C5 alkyl and R = H, Me or Ph in the single case when Ar = Ph, R = H and R = Ph, the product was diethyl (2-phenylethenyl)phospho-... 

---