Iodine with phosphites

Apart from their behaviour as ligands in metal catalyst systems, studies of the reactivity of phosphites towards a wide variety of other substrates have attracted attention. New aspects and applications of the classical Michaelis-Arbuzov reaction and its variants continue to appear. Evidence of the thermal disproportionation of methyltriaryloxyphosphonium halides formed in the reactions of triarylphosphites with alkyl halides, together with the formation of P-O-P intermediates, has been reported. The Michaelis-Arbuzov reaction has been used in the synthesis of phosphonate-based styrene-divinylbenzene resins and polyphosphonated chelation therapy ligands.Treatment of electron-rich benzylic alcohols dissolved in triethylphosphite with one equivalent of iodine affords a low-temperature one-pot route to the related benzylic phosphonates, compounds which are otherwise difficult to prepare. Upper-rim chloromethylated thiacalix[4]arenes have also been shown to undergo phosphonation on treatment with a phosphite ester in chloroform at room temperature. The nickel(II)-catalysed reaction of aryl halides with phosphite esters in high boiling solvents, e.g., diphenyl ether, (the Tavs reaction), has also... 

The Letsinger-Caruthers synthesis is unrelated to the biochemical one except in the area of efficiency. Because phosphites are so reactive, they would be totally unsuitable for the genetic tape itself, but because they are so reactive, they are ideally suited as intermediates in the chemical synthesis of polynucleotides. One can accomplish the needed condensation reactions with phosphites under strictly anhydrous conditions with very weakly acidic catalysts, and then stabilize the product by a mild oxidation of the phosphite to the desired phosphate with iodine. 

Kim, D.Y, Mang, J.Y, and Oh, D.Y, Reaction of silyl enol ethers with phosphite using hypervalent iodine compound. A new synthesis of 2-aryl-2-oxoalkylphosphonates, Synth. Commun., 24, 629, 1994. Hohnquist, C.R., and Roskamp, E.J., Tin(II) chloride catalyzed addition of diazo sulfones, diazo phosphine oxides, and diazo phosphonates to aldehydes. Tetrahedron Lett., 33, 1131, 1992. 

The oxidation-reduction condensation with phosphites and iodine has also been applied to the polycondensation reaction of o-amino acids, but the polymer produced is of low molecular weight27. ... 

Systems involving oxidative cleavage of metal-metal bonds have been studied by Poe s group.The order of reactions of bromine and iodine with dimetal carbonyls (M = Mn and/or Re) containing axial phosphines and phosphites, L, indicate the initial formation of adducts which may contain several molecules of Hal2 as in, e.g., equations (44) and (45) ... 

For phosphites Treat 10 ml of a solution containing 0 1 g with 10 ml of 5 per cent sodium bicarbonate solution and 20 ml of 0 1N iodine for two hours. Add 10 ml of 10 per cent acetic acid and titrate the excess of iodine with 01N thiosulphate. 1 ml O-IN = 0 004100 g H3PO3. 

The aHphatic iodine derivatives are usually prepared by reaction of an alcohol with hydroiodic acid or phosphoms trHodide by reaction of iodine, an alcohol, and red phosphoms addition of iodine monochloride, monobromide, or iodine to an olefin replacement reaction by heating the chlorine or bromine compound with an alkaH iodide ia a suitable solvent and the reaction of triphenyl phosphite with methyl iodide and an alcohol. The aromatic iodine derivatives are prepared by reacting iodine and the aromatic system with oxidising agents such as nitric acid, filming sulfuric acid, or mercuric oxide. 

Manufacture. Trichloromethanesulfenyl chloride is made commercially by chlorination of carbon disulfide with the careful exclusion of iron or other metals, which cataly2e the chlorinolysis of the C—S bond to produce carbon tetrachloride. Various catalysts, notably iodine and activated carbon, are effective. The product is purified by fractional distillation to a minimum purity of 95%. Continuous processes have been described wherein carbon disulfide chlorination takes place on a granular charcoal column (59,60). A series of patents describes means for yield improvement by chlorination in the presence of dihinctional carbonyl compounds, phosphonates, phosphonites, phosphites, phosphates, or lead acetate (61). 

The disadvantage of this method is that the dichloridites and monochloridites are sensitive to water and thus could not be used readily in automated oligonucleotide synthesis. This problem was overcome by Beaucage and Caruthers, who developed the phosphoramidite approach. In this method, derivatives of the form R 0P(NR2)2 react with one equivalent of an alcohol (catalyzed by species such as l//-tetrazole) to form diesters, R OP(OR")NR2, which usually are stable, easily handled solids. These phosphoroamidites are easily converted to phosphite triesters by reaction with a second alcohol (catalyzed by l//-tetrazole). Here, again, oxidation of the phosphite triester with aqueous iodine affords the phosphate triester. Over the years, numerous protective groups and amines have been examined for use in this approach. Much of the work has been reviewed. ... 

Step 4 With the coupling accomplished, the phosphite product is oxidized to a phosphate by treatment with iodine in aqueous tetrahydrofuran in the presence of 2,6-dimethylpyridine. The cycle (1) deprotection, (2) coupling, and (3) oxidation is then repeated until an oligonucleotide chain of the desired sequence has been built. 

Kinetic studies of the oxidation of phosphites such as triisopropyl phosphite with BTSP 1949 to give phosphates such as triisopropyl phosphate [177] led to the discovery that oxidation of diphosphite nucleotide intermediates such as 2008 with BTSP 1949 at -20 °C in the presence of TMSOTf 20 (instead of iodine in... 

When an ethereal solution of iodine is added to triethyl phosphite a rapid reaction ensues, the iodine being taken up quantitatively in accordance with the equation1... 

Of course, the product does not have a phosphate linker between the two nucleosides, and phosphorus is still in the wrong oxidation state. This is remedied by oxidation of the dinucleotide phosphite to a phos-photriester using iodine. We now have the required phosphate linker, though it is still protected with the cyanoethyl group. This is retained at this stage. 

The yellow crystalline azaberbinone (388) has been prepared by several, closely related methods. Dehydrogenation of betaine 378 (Section III,E,2) with dichlorodicyanoquinone gives compound 388 directly. Alternatively, this compound (388) has been prepared in three ways from 6 -nitropapaverine (385) (Scheme 15) (i) Treatment of compound 385 with triethyl phosphite gives a low yield of betaine 388 directly (ii) compound 385 in methanolic KOH at reflux temperature gives the anthranil 386 which rearranges to the betaine 388 in hot triethyl phosphite and (iii) iodine oxidation of 6 -nitro-papaverine (385) generates the A-oxide 387 which is reduced to the betaine 388 by sodium bisulfite. The chemistry of compound 388 remains unexplored. 

The chemical basis for the phosphite triester approach is the observation, that dialkyl phos-phorochloridites such as (CjHjOJjPCI react very rapidly at the 3 -OH of nucleosides in pyridine even at low temperatures. In contrast, the reactions of analogous chloridates, e.g. (C2HjO)2POCIi require several hours at room temperature. It was later found that phosphite esters can be oxidized quantitatively to the phosphates by using iodine in water and that clean condensation of phosphorochloridites with nucleosides can be achieved in THF at -78 °C. To develop this chemistry into a useful synthetic procedure it was necessary to establish which... 

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