Phosphonates, fluorinations

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). 

Scheme 11 Preparation of fluorinated phosphonates involving phosphonyl and phospho-ranyl radicals as chain carriers...

Halogenoalkyl and Related Acids. Fluorinated phosphonates are often designed as a new class of biological phosphate mimics. They are used as enzyme inhibitors and metabolite probes. Therefore, these compounds have attracted much attention. During the period of this review a number of new methods of synthesis, including the preparation of novel fluorinated phosphonates, have been reported. A complementary triflate displacement approach to (a-mono-fluoroalkyl) phosphonates (219) has been elaborated. Treatment of alkyl triflates or iodides with the potassium salt of (a-fluoro-a-phenylsulfonylmethyl) phosphonate (220) yields (a-fluoro-a-phenylsulfonylalkyl) phosphonates (221), which can be cleanly desulfonated affording (219) (Scheme 58). 

Patois. C., and Savignac, P, Easy access to a-fluorinated phosphonic acid esters, Phosphorus, Sulfur Silicon Relat. Elem., 77, 163, 1993. 

A second methodology has recently been developed that is best suited to nonstabilized and semistabilized phosphonate carbanions. It involves an initial silylation in the presence of an appropriate base (LDA or LiHMDS) followed by fluorination of the protected carbanions. The resulting fluorinated phosphonates are easily desilylated to afford pure a-monofluorophosphonates in good to excellent yields (68-97%, Scheme 3.25). 5 ... 

Chambers, R.D., and Hutchinson, J., Preparation of fluorinated phosphonate compounds, F2 Chemicals, Int. Patent Appl. WO 9905080, 1999 Chem. Abstr., 130, 139451, 1999. 

Wnuk, S.F., Bergolla, L.A., and Garcia, P.L, Jr., Studies toward the synthesis of a-fluorinated phosphonates via tin-mediated cleavage of a-fluoro-a-(pyrimidin-2-ylsulfonyl)alkylphosphonates. Intramolecular cyclization of the a-phosphonyl radicals, J. Org. Chem., 67, 3065, 2002. 

Berkowitz. D.B.. Eggen, M., Shen. Q.. and Shoemaker, R.K., Ready access to fluorinated phosphonate mimics of secondary phosphates. Synthesis of the (a,a-dilliioroalkyl)phosphonalc analogues of l-phosphoserine. L-phosphoallothreonine. and L-phosphothreonine, J. Org. Chem., 61, 4666, 1996. 

Blackburn [67] and McKenna [68] therefore suggested that a-fluorination would lead to better phosphate mimics a-fluoromethylphosphonates, in particular, would match the second pK, of a phosphate group ( isoacidic ), whereas , -difluoro-methylphosphonates would better match the electrostatic potential surface of the bridge ( isopolar ) (Figure 4.21). In contrast with the methylphosphonate congener the a-fluorinated phosphonates [69] can also act as hydrogen-bridge acceptors [36, 5, 70]. 

Another interesting class of substrates was identified with p-keto phosphonates, as fluorinated phosphonates represent important mimics for phosphates in drug... 

The Phospha-Michael addition in organic synthesis and biomedical application of fluorinated phosphonates have been the subject of two reviews. ... 

Scheme 1.10. High stereoselectivity using a-fluorinated phosphonates in the Horner-Wadsworth-Emmons reaction.

The reaction of perfluoroalkyl iodides with alkenes affords the perfluoro-alkylated alkyl iodides 931. Q.a-Difluoro-functionalized phosphonates are prepared by the addition of the iododifluoromethylphosphonate (932) at room temperature[778], A one-electron transfer-initiated radical mechanism has been proposed for the addition reaction. Addition to alkynes affords 1-perfluoro-alkyl-2-iodoalkenes (933)[779-781]. The fluorine-containing oxirane 934 is obtained by the reaction of allyl aicohol[782]. Under a CO atmosphere, the carbocarbonylation of the alkenol 935 and the alkynol 937 takes place with perfluoroalkyl iodides to give the fluorine-containing lactones 936 and 938[783]. 

The anions of malonaldehyde [106, 107] and of organophosphonates [108, 109, 110] are fluorinated in good yields to provide interesting fluorinated intermediates The At-fluoro compound B in Table 3a is also effective in the fluonnation of phosphonate anions [109] (equations 60 and 61). 

Trifluoromethyl or pentafluorophenyl phosphonates can be produced photo-chemically by irradiation of triethylphosphites with fluorinated iodides [181] (equation 48). 

Nitrogen- or Fluorine-Containing Phosphonates In N-containing phosphoric acid esters an >NH or >NR group is used instead of the bivalent >0. A typical reaction is the transformation of POCl3 with primary or secondary amines to the corresponding amides see Eq. (73) ... 

Depression of the surface tension of their aqueous solutions and other surface-active properties are given in Chap. 4. When fluorine is changed for hydrogen in the alkyl chain of a phosphonate the compound becomes less heat-sensitive. Often the surface tension of aqueous solutions of these compounds is very low. 

An improved route to fluorinated 4-hydroxycoumarins has been reported, based on a facile decarboxylation-deacetylation of their 3-(3-oxopropanoic acid) derivatives <96TL15S1>. The reaction of methyl salicylates with triphenylphosphoranylidene ketene, Ph3P=C=C=0, affords 4-methoxycoumarins <96JCS(P1)2799> and the formation of coumarin 3-phosphonates from salicylaldehydes and phosphonoacetates, Et02CCH2P(0)(0R)2, has been investigated <96T12597>. 

Beside thioamides, dithioesters are the most stable and accessible thiocarbonyl compounds. Their specific reactivity, in particular towards nucleophiUc reagents and their apphcations to the formation of carbon-carbon bonds, have already been reviewed [8]. However, as shown below, the presence of a phosphonate function alpha or beta to the thiocarbonyl group in phosphonodithioformates and phosphonodithioacetates makes these difunctional compounds very versatile building blocks. Moreover, for the phosphonodithioacetates, the substitution of the methylenic hydrogen atoms by fluorine increases again their potential as intermediates for the synthesis of modified natural and bioactive phosphorylated structures. 

The kinetics of deuterium isotope exchange between diphenyl phosphine and t-butylthiol have been studied by H n.m.r. spectroscopy.274 A negative temperature coefficient was observed for the reaction of a perf1uoroalky1 phosphite with a fluorinated aldehyde.275 The kinetics for the reaction of alcohols with phosphoryl trichloride bore strong similarities to those of carboxylic acid derivatives.276 An interesting report desribed the solvolysis of ary 1 hydroxymethyl-phosphonates. It was shown that a phosphoryl group does not prevent carbocation formation on an immediately adjacent carbon atom.277... 

There do not appear to be any simple phosphines that bear a CH2F group. However, fluorine NMR spectra of phosphonates, phosphane oxides, and phosphonium compounds with CH2F and —CHF- bound to phosphorous have been reported. Examples are given in Scheme 3.26, including spectral data for the useful Horner-Wadsworth-Emmons reagent, triethyl 2-fluoro-2-phosphonoacetate. 

At the end of the 1990s statistics show that the non-ionic surfactants achieved the highest growth in production rates world-wide, though anionic surfactants (anionics) maintained the dominant position in the surfactant market. Today they are produced in a larger variety by the petrochemical industry than all other types of surfactants. Their production spectrum covers alkyl sulfates (ASs), secondary alkane sulfonates (SASs) and aryl sulfonates and carboxylates via derivatives of partly fluorinated or perfluorinated alkyl surfactants to compounds with an alkylpolyglycolether substructure combined with an anionic moiety such as alkylether sulfates (AESs), phosphates, phosphonates or carboxylates. 

Fluorinated phosphinic and phosphonic acid derivatives Perfluoro derivatives of alkyl phosphonic acid CnF2n+1-P(0)(0H)2 and alkyl phosphinic acid CnF2n+i(CmF2m+1)-P(0)0H (n = m or n m) shown with their general structural formulae in Fig. 2.11.29(1) and (II) were examined by negative ESI- and APCI-FIA-MS. These anionic surfactant compounds contained perfluoro alkyl chains [2,22,25]. By analogy with their behaviour in the TSI-FIA-MS(—) process [25], the phosphonic acid formed [M — H] ions at m/z 399 and 499... 

The mixture of anionic fluorinated alkylphosphinic and -phosphonic acid surfactants with perfluorinated alkyl moieties was examined using ESI-FIA-MS-MS(—). For CID in the negative mode, precursor ions at m/z 399, 499 and 599 were selected [22]. From all precursor ions only one product ion at m/z 79 ([PO3]—) besides the [M — H] ion was... 

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