Phosphoramidites, protonation

These results prove that with these phosphoramidites protonation at the phosphorus atom takes place. When different alcohols were subjected to the reaction with a given phosphoramidite, the most acidic alcohol, namely phenol, reacted the best. In this case, autocatalysis has to be taken into consideration. Steric bulk decreases the reactivity. 

A variety of substrates has been used in this type of conjugate addition reaction with trialkyl phosphites, with assorted proton sources.361 384 Other types of trivalent phosphorus reagents without acidic (or conjugate base of acidic) sites have also been used successfully for this conjugate addition process, including triaryl phosphites (without dealkylation),369 phosphoramidites,385 389 phospho-nites,363 380 390 and phosphinites.360 380... 

Except for one recent example, all iridium-catalyzed allylic substitution reactions have been performed under an inert atmosphere with dry solvent and reagents. The iridium metalacycle is sensitive to protonation, which opens the metalacycle and results in the formation of a less-active complex containing a K -phosphoramidite ligand. A paper by Helmchen et al. addressed this issue [107]. Nearly all iridium catalysts used for allylic substitution consist of an iridium fragment chelated by COD. In the presence of a catalyst containing dibenzo[a,c]cyclooctatetraene (dbcot) in place of COD, allylic substimtion reactions occur in air with results that are comparable to those of reactions performed under an inert atmosphere (Scheme 35). 

Once again, the zinc enolates generated in the conjugate addition can be trapped with various electrophiles besides protons. For example, reaction of the enolate 270 obtained by treating cyclohex-2-enone with dimethylzinc in the presence of Cu(OTf)2 and phosphoramidite 269 with trimethylsilyl triflate and diiodomethane provided the cyclopropanation product 271 with good diastereoselectivity and high enantiomeric excess and chemical yield... 

Mechanistic Studies. - The mechanism of the reaction of tetra-zole-activated phosphoramidites with alcohols has been studied. A series of diethyl azolyl phosphoramidites (85) was prepared from diethyl phosphorochloridite and fully characterized, and the same compounds shown to be formed from the phosphoramidite (86) and azole. The degree of formation of (85) from (86) increases with the acidity of the azole, and the proposed mechanism is a fast protonation of (86), followed by a slow, reversible formation of (85) and a fast reaction of (85) with alcohols. Another study was concerned with the influence of amine hydrochlorides on the rate of methanolysis of the phosphoramidites (87) or (88), or tris(diethylamino)phosphine.The chloride content was measured to be 10-20 mM in doubly distilled samples which explains that "uncatalysed alcoholysis is possible. Intensive purification, including treatment with butyllithium and distillation from sodium, brought the chloride content down to 0.1-1 mM. The methanolysis reaction, in methanol as the solvent, was found to be first-order in catalyst concentration. An aJb initio calculation on N- and P-protonated aminophosphine (89) gave similar proton affinities for N and P this contrasts with earlier MNDO calculations which had ff-protonated species as the most stable. The M-protonated compound had an electronic structure reminiscent of a phosphenium ion-ammonia complex. 

Mechanistic Studies. - A kinetic study of the solvolysis of the cyclic phosphoramidite (65) in methanol at 40 °C, catalysed by different amine hydrochlorides, showed that kcat obeyed the Bronsted equation with a = 0.65. This means that a proton transfer is well advanced in the TS, which was depicted as (66). Reactions of phosphoramidites with phenols are not catalysed by amine hydrochlorides and proceed sluggishly without a solvent aromatic solvents, e.g. 

The novel dinucleotide phosphoramidate (78) has been obtained from the phosphoramidite dimer (79) upon reaction with methoxymethylene ethanolamine in the presence of tetrazole, followed by iodine oxidation in the presence of the same amine. Since the two amino substituents are identical it is envisaged that in aqueous solution, rapid proton transfer between the two phosphoramido moieties will render the molecule achiral at phosphorus. 

DNA strands, like polypeptides (Section 4.4), can be synthesized by the sequential addition of activated monomers to a growing chain that is linked to an insoluble support. The activated monomers are protonated deoxyri-bonucleoside 3 -phosphoramidites. In step 1, the 3 phosphorus atom of this incoming unit becomes joined to the 5 oxygen atom of the growing chain to form a phosphite triester (Figure 6.7). The 5 -OH group of the activated... 

In the area of trivalent phosphorus acid chemistry some very unusual reactions have been reported from combinations of 4-dimethylamino-pyridine (DMAP) with phosphorus trichloride. In one case a phosphide and free chlorine are claimed to be formed The extreme nucleofugicity of a tervalent phosphorus atom bearing two DMAP groups also stimulates an unprecedented Arbusov reaction of a tervalent derivative. Another surprise is that, although the reaction is certainly acid-catalysed, the mechanism of substitution at phosphoramidites does not involve either P- or N-protonated species. A final surprise in this area is the preparation, by Russian chemists, of some tervalent phosphorus compounds which apparently contain P-OH groups. 

Each phosphoramidite is coupled to the anchored nucleoside by a reaction in which the free 5 -OH of the anchored nucleoside displaces the diisopropylamino group from phosphorus (Figure 26.16). The coupling is catalyzed by tetrazole, which acts as a weak acid to protonate the diisopropylamino group. 

Selective Phosphitylation of the Primary Hydroxyl Group of Nucleosides. 5-Ethylthlo l//-tetrazole has been used for the selective S -phosphitylation of nucleosides. The commonly accepted mechanism involves protonation of a phosphoramidite by the weakly acidic tetrazole, followed by nucleophilic attack by tetrazollde ion giving a tetrazoyl phosphoramidite (2) (eq 2). The nucleophilic attack of the 5 -hydroxyl group then produces the phosphite triester, which is then carried through further transformations (eq 3). ... 

The protonation of one oxygen atom in the first step is a less likely event, but it has to be considered in the hydrolysis of phosphoramidites, where preferred protonation of the stronger base nitrogen is possible (see also Section 2.3.3). Therefore, phosphoramidites could be even more sensitive to acids than phosphites... 

Nifant ev and coworkers [37] were able to isolate P-protonated salts after treatment of phosphoramidites with HBF4. Such BF4 salts can even be crystallized from alcohols [38] Calculations with H2P-NH2 showed that protonation of the phosphorus causes a shortening of the P-N bond. This has been observed with BF4 salts by IR spectroscopy because of a characteristic band at 2450 cm" [39]. 

Dahl suggested a kinetic model for the nucleophilic substitution reaction at tri-covalent phosphorus with a P-N bond with alcohols (Scheme 2.135) [41]. The reaction proceeds in the presence of an ammonium salt as a catalyst. In the first step, the phosphoramidite is protonated in a fast equilibrium (1). In the second step, replacement of the amino group takes place (2). This step is slow and is the rate-determining step. Regeneration of the catalyst in the last step closes the catalytic cycle (3). 

Phosphoramidites undergo alcoholysis in the absence of acids only in protic solvents [42]. The rate depends on the pK, value of the alcohol. l//,l//-Heptafluorobutanol [pK j o) = 12]. with similar acidity as phenol [P arHjO) 11 ] replaces the amino group [43] in contrast to tert-butyl alcohol [P arHjO) = 19.2], which does not react [44]. An aniline substituent was displaced faster than a more basic alkyl amine. This result could be a counter-argument against the first protonation of the amine, but it should be kept in mind that the aniUnium salt is more acidic than the ammonium salt containing the amidite [45]. 

In oligonucleotide chemistry, alcoholysis of phosphoramidites is widely used for the construction of the polymers from monomeric sugars (Scheme 2.136) [46]. The reaction is usually catalyzed by Lff-tetrazol (TetH), which in the first step protonates the amino group. Subsequently, the tetrazole anion replaces the amine. The dinucleoside phosphite is formed by the final reaction with the alcoholic group of a second nucleoside. Since the formation of the tetrazole phosphoramidite from the intermediate salt is rate-determining, the catalyst... 

Diastereomers of deoxynucleoside 3 -(0-P-cyanoethyl, N-diisopropyl)-phosphoramidites can be separated by chromatography. The proton n.m.r. spectra show characteristic differences which can be used to assign absolute configurations at phosphorus.a study has been reported on the use of such intermediates for oligoribonucleotide synthesis. 1 4... 

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