Phosphonate esters cleavage

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

Quite recently it was shown that phosphonic esters, trimethylsilyl [124, 143] and alkyl esters [124,143, 145] could also be used to modify the surface of titanium or aluminum oxide in organic solvents at moderate temperatures. Unlike Si-O-C bonds, P-O-C bonds are not easily hydrolyzed, and their cleavage on an oxide surface was unexpected. Most probably, coordination of the phosphoryl oxygen to the surface assists the condensation by increasing the electrophilicity of the P atom, thus facilitating the condensation of P-0-R groups with surface hydroxyls (Scheme 7) [124]. The chemisorption of... 

Demethylation of, POCH3. Phosphate and phosphonate esters are partially dealkylated by tertiary amines. r-Butylamine is superior Tor this cleavage, and it is very selective. Only O—Cl I3 bonds are affected ethyl esters are stable to the amine for several weeks. A benzyl group can be cleaved under forcing conditions.1 [Examples ... 

In the covalent approach, the print molecules are covalently coupled to polymerisable molecules prior to polymerisation (see Chapter 4). The covalent bonds have to be relatively easy to break to allow cleavage of the print molecules after polymerisation. Print molecules have been coupled to monomers through the formation of boronic, carboxylic and phosphonic ester bonds, amide bonds, imines and ketals. After copolymerisation with a high degree of cross-linker, the print molecules are cleaved from the polymer. A representative example of the covalent approach is shown in Fig. 17.1. 

This reaction has been utilized in the context of natural product synthesis. A recent example is the synthesis of colletodiol by Keck, shown in equation (45). In this example, no problems were encountoed with epimerization or ester cleavage. The desireid ( )-ester (182) was synttesized in 80% yield. Two examples are outlined (in equations 46 and 47) in which epimerization was a substantial problem with sodium or potassium salts, while the LiCl/amine method effectively suppressed this side reaction. When the phosphonate was allowed to react with the cyclohexanal derivative (183), the sodium salt gave epi-merized material. Use of LiCl and diisopropylethylamine gave an 88% yield of alkene (184), free of epimer (equation 46). In the synthesis of norsecurinine, Heathcock found that the phosphonate anion... 

The first step of the mechanism is the nucleophilic attack (Sn2) of the alkyl halide by the phosphorous to form a phosphonium salt A. Under the reaction conditions (heat) the phosphonium salt A is unstable and undergoes a C-0 bond cleavage (the halide ion (X ) acts as a nucleophile and attacks one of the alkyl groups in an Sn2 reaction) to afford the phosphonate ester. 

Other EWG which migrate readily upon (3-cleavage of an epoxide include the phosphonate ester (equation 57), sulfoxide (equation 58) and sulfone (equation 59). ... 

Hydration in the presence of mercury(II) sulphate yields an (oxoalkyl) compound (equation The treatment of the phosphonic ester 364 (R = Et, Z= P03Et2) with a thiolate leads, via diethyl ethynylphosphonate, to the ethenylphosphonic diester 365 with the concomitant formation of thiophosphate ester in this particular case, the product 365 as initially formed, is of Z geometry, but isomerizes when distilled . In other cases of the reactions with thiols, for instance with 364 (R = Et, Z = Cl), the direct replacement of Z is accompanied by overall displacement plus addition at each carbon to give products of types 366 (as a mixture of E and Z stereoisomers) and 367. The same substrate 364 (R = Et, Z = Cl) with the monosodium salt of ethane-1,2-diol represents an alternative route (substitution followed by addition) to 361, but with more basic nucleophiles such as Bu O, and even MeO , cleavage of the phosphorus-carbon bond occurs, although the extent of this decreases, and the extent of addition (with EtO and PhO ) increases, when R = Me is replaced by R = Et. The additions of arylsulphenyl chlorides to 364 (R = Et, Z = Me) occur stereoselectively to give only the E products . 

A study of the alkaline hydrolysis of the phosphonate ester(480) examined the possibility of involvement of dianionic or hexacoordinate species during the reaction. Compound (488) was formed by P-O bond cleavage rather than by cleavage of the C-O bond. Al.so observed was (489), formed under locally high concentrations of (480) by its reaction with (488). (491) was also observed its formation could re.sult from the cyclization of (489) to (490) with subsequent hydrolysis. The formation of intermediate... 

In Situ Generation of lodotrimethylsilane. Of the published methods used to form TMSI in situ, the most convenient involves the use of TMSCl with Nal in acetonitrile. This method has been used for a variety of synthetic transformations, including cleavage of phosphonate esters (eq 23), conversion of vicinal diols to alkenes (eq 2A), and reductive removal of epoxides (eq 25). ... 

Cleavage ofPhosphonate and Phosphate Esters. Phospho-nate and phosphate esters are cleaved even more readily with TMS-I than carboxylic esters. The reaction of phosphonate esters proceeds via the silyl ester, which is subsequently hydrolyzed with MeOH or H2O (eq 14). 

Phosphorus-containing compounds provide useful substrates for ozonolysis reactions as well and can provide several products depending on the reaction workup. Several biological uses exist for -amino-a-hydroxy phosphonic acid derivatives and they can be readily prepared by ozonolysis of Al-(ethoxycarbonyl)-/3-amino-Q -methylene phosphonic esters after reductive workup with sodium borohydride (eq 54). When the reaction mixture is treated with sodium hydroxide in MeOH, an anomalous ozonolysis reaction occurs and cleavage of the methylene as well as the carbon-phosphorus bond occurs to yield (V-(ethoxycarbonyl)-a-amino methyl carboxylic esters. 

The target polymer was prepared by bromotrimethylsilane-induced cleavage of the n-butyl phosphonate ester groups in neutral precursor polymer. After neutralisation of the reaction mixture with aqueous sodium hydroxide, the target polymer has exhibited good solubility in water. 

Catalytic antibodies have been produced to catalyze an impressive variety of chemical reactions. For instance, stable phosphonic esters (or lactones, respectively) have been used as transition state mimics for the hydrolysis of esters and amides [555-557], acyl transfer [558] and lactonization [559] reactions, which all proceed via a tetrahedral carbanionic intermediate. In some instances, the reactions proved to be enantiospecific [560]. Elimination reactions [561, 562], reductions [563], formation and breakage of C-C bonds [564,565] and even photochemical reactions [566] can be catalyzed. The cleavage of an ether [567] and cis-trans isomerization of alkenes have been reported [568]. 

The copolymer with poly(phosphonic) acid in the ester form (structure 5) showed a first degradation step between 250 and 350°C. The magnitude of the step was directly correlated with the phosphonate ester content. This degradation was ascribed to the decomposition of the ester units to form ethylene and phosphonic acid units, possibly followed by a subsequent formation and loss of water, by self-condensation at these high temperatures. A second degradation step was noted between 350 and 400 C, most probably connected with the cleavage of the C-P bond. The copolymers in the acid form showed a small initial weight loss already from 150°C, ascribed to reversible self-condensation and desorption of... 

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