Phosphorylation of alcohols

The decomposition of (536) with hydrogen sulfide yields pyrazole (76T1909). The 1-phosphorylpyrazoles (537) are suitable reagents for the phosphorylation of alcohols, amines, hydrazines and azides (76AG(E)378). 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

The use of triphenylphosphine and 2,2 -bipyridyl disulphide in oxidation-reduction condensations has been extended to the phosphorylation of alcohols and phosphates, and to the preparation of 5 -(2-pyridyl) phosphorothioates (60) which have been used for the synthesis of pyrophosphates (see Chapter 6, Section 1). 

The phosphorylation of alcohols by CEP-imidazole (41 X=N) with CEP-ring retention is already well-established. Following from the observation that CEP-pyrrole (41 X=CH) phosphorylates alcohols with CEP-ring opening, an explanation has been advanced based upon the differences in apicophilicities of the pyrrole and imidazole moieties in pentaco-ordinate intermediates (Scheme 10). A scale of relative reactivities based upon the reactions in the equations... 

Analogously to the phosphorylation of alcohols with phosphoric azolides the phos-phinylation is carried out by means of phosphinic azolides (CH2CI2/C2H5OC2H5). In the following case a I2/C2H5OC2H5) protonated diphenylphosphinic imidazolide is used to give the allylic diphenylphosphinic esters in good yields ... 

Despite the aromatic character, the arylphospholes could also participate in Diels-Alder reactions to give new type of 7-phosphanorbomenes. These products together with phosphanorbomenes obtained by the regio- and stereospecific dimerization of arylphosphole oxides were useful model compounds in the UV light mediated fragmentation-related phosphorylation of alcohols. A novel mechanism was substantiated. 

Atherton, F.R. and Todd, A.R., Phosphorylation. M. Reactions of phosphites with polyhalogen compounds in the presence of bases and its application to the phosphorylation of alcohols,. Chem. Soc., 674, 1947. 

Atherton-Todd phosphorylation of alcohols and phenols (Table 3.22)... 

The above reagents serve as condensing reagents and have different reactivities for peptides 279, p-lactams 281, esters, thioesters, and mixed phosphates, as well as for the direct preparation of 3-acyl-2(3F/)-oxazolones. The bis(2-oxo-3-oxazohnyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67). ... 

Perich, J.W. and Johns, R.B. (1988) Di-ferf-butyl WA-diethylphosphoramidite. A new phosphitylating agent for the efficient phosphorylation of alcohols. Synthesis 142-144. 

Phosphorylation. Dibenzyl phosphorochloridate is widely used for phosphorylation of alcohols, but is more difficult to prepare than the fluoridate. Phenol is very readily phosphorylated by 1 and CsF in CH3CN, and indeed a phenolic hydroxyl group is selectively attacked even in the presence of a primary hydroxyl group. Primary and anomeric alcohols are preferentially phosphorylated in the presence of a secondary hydroxyl group. Alcohols that are insoluble in acetonitrile can be phosphorylated by 1 and DBU in place of CsF. 

Phosphorus is abundant on Earth, both as an element (the llth-most abundant atom in Earth s crust) and as phosphate. Meteorites hold a variety of phosphate-containing minerals and some phosphide minerals.10 Scientists at the University of Arizona have recently suggested that Fe3P, the mineral schreibersite, leads to the formation of phosphate and phosphite when corroded in water. Although phosphorylation of alcohols was not demonstrated, mechanistic considerations suggest that it should be possible. It is noteworthy that a clear prebiotic pathway for the chemical incorporation of phosphate into RNA or DNA has not been found. No nucleosides (nucleobases joined to sugars) have been reported from meteorites. Nor has evidence been found in any meteorite of the presence of nucleosides or nucleotides (nucleosides attached to phosphates). That suggests that nucleic acids were first formed as products of metabolism. 

Phosphorylation of alcohols and amines forming mixed esters of phosphoric acid and phosphorami-dates, respectively, is effected by triphenylphosphine and 2,2 -dipyridyl disulfide. The reaction passes through a triphenylphosphonium phosphate of type (68 equation 44) as an active intermediate. Formation of an intemucleotide linkage can be achieved by this method. °° Dimerization of monoesters of phosphoric acid producing dialkyl pyrophosphates is achieved using tributylphosphine and dibenzoyl-ethylene or p-quinonedibenzimide (equation 45). A phosphonium phosphate is the active intermediate of this reaction. ... 

Phosphorylation of alcohols can also be achieved through the phosphitylation with some kinds of tri-valent phosphorus reagents followed by oxidation. The phosphitylating agents are generally more reactive than the corresponding pentavalent analogs. Thus this approach has been used very frequently for the preparation of phosphoryl derivatives of less reactive alcdiols, such as nucleosides. ... 

Protection or reductive deoxygenation of alcohols and ketones. Ireland et al.2 have found that N,N,N, N -tetramethylphosphoroiiamidates (TMPDA derivatives) of alcohols and of ketone enolates are reduced in high yield by lithium-ethylamine. They are readily prepared by phosphorylation of alcoholate or enolate anions. The complete sequence is as follows. The alcoholate anion is simply prepared by treatment of an alcohol with a slight molar excess of n-butyllitliium. The enolate anions of saturated ketones are prepared by treatment with lithium diisopropylamide. In the case of a,/J-unsaturated ketones, lithium-ammonia reduction or conjugate organometallic addition is suitable. For phosphorylation of the Jnion a fivefold excess of N,N,N, N -tetramethyldiamidophosphorochloridate in 4 ] dimethoxyethane (or THF)-N,N,-N. N -tetramethylethylenediamine (TMEDA) is used. The reaction is complete after... 

Phosphorylation of alcohols. A mixture of ethanol, the chloride (1), and 2,6-lutidine (2) was refluxed, the solution was evaporated, and the ethyl phosphoro-dimorpholidate (3) extracted with ether and distilled. Hydrolysis to the dihydrogen... 

Phosphorylation of alcohols by the reagents (9 R=Oalkyl) in aprotic solvents is catalysed by acetate ion, probably through penta- and hexa-co-ordinate intermediates (Scheme 1) that by the corresponding aryl esters is catalysed by phenoxide... 

The complex formed between diethyl azodicarboxylate and triphenylphosphine is a very useful reagent for condensation reactions. The reaction of alcohols with phthalimides, in the presence of diethyl azodicarboxylate and triphenylphosphine, resulted in the formation of the corresponding AT-alkylphthalimide in good yield. The reaction proceeds stereospecifically with complete inversion, as shown by conversion of (5 )-(+)-2-octanol to )-2-octylamine, isolated by treatment of the initially formed phthalimide with hydrazine hydrate. Condensation between alcohols and other active-hydrogen compounds using the same reagents has also been described (Scheme 1). Phosphorylation of alcohols by initial activation... 

Examples of bioorganic reactions of metaphosphate as liberated by ATP are the phosphorylation of alcohols in the presence of zinc salts, the imidation of esters, and the reversible phosphorylation of hydroquinone, which acts as a phosphorylating agent in the presence of oxidants ( oxidative phosphorylation ), (Cooper et al, 1968 Sigman et al., 1972). 

Phosphorylation of alcohols [93] and phenols [94] using n-tetrabutylanunonium bromide as a phase-transfer catalyst has also been reported. The mixed trialkyl phosphates obtained using this procedure are also of high purity. Hydrazine has also been successfully phosphorylated under phase-transfer conditions yielding the corresponding phosphor-amide hydrazides [95]. 

Phosphorylation of Alcohols with A Phosphoryloxazolidi-nones. This reaction can be efficiently performed by using copper(II) triflate as catalyst, and the conditions are milder than those errqiloyed with alkoxides. Phosphoryl transfer from N-phosphoryl 5,5-diphenyl oxazolidone is an important process in S3mthesis of biomolecules. The optimal ligand is A(,A -ethy lenebis-(benzaldimine)(BEN) with 0.2 equiv of Cu(OTf)2 as the best catalyst (eq 37). The ligand-bound Cu species activates the P=0 bond for nucleophilic attack by the alcohol. 

In 2005, Kosma et al. [9] employed the same alcohols 4 and 7 as intermediates to prepare D-glycero-D-mowwo-heptose-7-phosphate 18 and other heptose derivatives [10]. The phosphorylation of alcohol 4 using the phosphoramidite procedure afforded the 7-O-phosphotriester 15 in 65% yield. The catalytic osmylation of the alkene provided a 1 4 mixture of 16 and 17 in 71% yield. After separation by chromatography, the catalytic hydrogenation of 17 in the presence of 10% Pd/C... 

Dimethylaniline Phosphorylation of alcohols via dithiophosphorous acid esters... 

There has been little development in the use of acid-labile protecting functions, and the benzhydryl [11] and t-butyl [12] groups described for this purpose some years ago have found little application. Phosphoramidates are sensitive to acid, and morpholine has been used as a protecting group in phosphorylations of alcohols [13]. The P—N bond is cleaved by treatment with an ion exchange resin. Nucleoside 5 -phosphoromorpho-lidates are susceptible to nucleophilic attack by phosphoric or pyrophosphoric acid to form nucleoside 5 -polyphosphates [14] (Fig. 6.5). 

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