Phosphoramidates amides

Carbodi-imides are used to mediate the formation of amide linkage betwen a carboxylate and an amine or phosphoramidate linkages between a phosphate and an amine [12]. The following is essentially the method of Rockwood [13] and is modified to give a phospho-diester link between the terminal monophosphate of the oligonucleotide and the hydroxyl group of 2-hydroxyethyl disulfide (HEDS) [14]. 

Cyclic phosphoramidates (phosphoric amides) were obtained by the reaction of amino alcohols with a phosphoric diimidazolide.tl933,[2]... 

The reaction of 151 with methanol to give dimethyl phosphate (154) or with N-methylaniline to form the phosphoramidate 155 and (presumably) the pyrophosphate 156 complies with expectations. The formation of dimethyl phosphate does not constitute, however, reliable evidence for the formation of intermediate 151 since methanol can also react with polymeric metaphosphates to give dimethyl phosphate. On the other hand, reaction of polyphosphates with N-methylaniline to give 156 can be ruled out (control experiments). The formation of 156 might encourage speculations whether the reaction with N,N-diethylaniline might involve initial preferential reaction of monomeric methyl metaphosphate via interaction with the nitrogen lone pair to form a phosphoric ester amide which is cleaved to phosphates or pyrophosphates on subsequent work-up (water, methanol). Such a reaction route would at least explain the low extent of electrophilic aromatic substitution by methyl metaphosphate. 

R = PhCHMe) have been prepared and distinguished by n.m.r. spectroscopy.31 Attempts to prepare 7V-aryl derivatives of cyclophosphamide by cyclization of the phosphoramides (36) proved unsuccessful.32 Although this type of reaction has proved to be of great value in the preparation of perhydro-l,3,2-oxazaphosphorines and 1,3,2-oxazaphospholidines when NaOEt, NaOH, or NaH are employed as reagent, in this instance the bis(chloroethyl)amide side-chain presents a further possible reaction site. However, steric effects, also considered as an explanation for instances of failure of the reaction (see Organophosphorus Chemistry , Vol. 7, p. Ill) may be operating adversely. 

In 2006, Yamamoto and Nakashima picked np on this and designed a chiral A -triflyl phosphoramide as a stronger Brpnsted acid catalyst than the phosphoric acids based on this concept. In their seminal report, they disclosed the preparation of new chiral BINOL-derived A -triflyl phosphoramides and their application to the asymmetric Diels-Alder (DA) reaction of a,p-unsaturated ketones with sily-loxydienes [83], As depicted in Scheme 59, chiral A-triflyl phosphoramides of the general type 4 are readily synthesized from the corresponding optically active 3,3 -substituted BINOL derivatives 142 through a phosphorylation/amidation route. 

Phosphoramidous fluorides, 13 383-389 Phosphoranes, 16 47 cage compounds, 30 246 as propellanes, 33 268 Phosphorescence, 19 68 Phosphoric acid ester amides, reaction with hexafluoroacetone, 30 237 Phosphoric acids, condensed, properties of, 5 220... 

The choice of these derivatives, namely, those formed from amines of moderate strength, appears to be the best compromise for the synthesis to be effective. Although the susceptibility of phosphor-amidates to attack by nucleophiles increases with enhancement of the basic strength of the parent amine,279 280 the reverse trend is observed for the yields of nucleoside 5 -phosphoramidates when they are prepared from nucleoside 5 -phosphates by condensation with the appropriate amines through the action of N,N -dicyclohexylcarbodi-imide.279... 

Acid fluorides can be used for a elean preparation of amides.9 96 The use of silylated amines is an elegant alternative, sinee liberated fluoride progressively desilylates them to more nucleophilic species. The reaction has to be started with a catalytic amount of fluoride (TBAF).92 Stannyl amines97 or phosphoryl amines (phosphoramides)98 have been used in similar reactions. 

Carbodiimides are used to mediate the formation of amide or phosphoramidate linkages between a carboxylate and an amine or a phosphate and an amine, respectively (Hoare and Koshland, 1966 Chu etal., 1986 Ghosh etal., 1990). Regardless of the type of carbodiimide, the reaction proceeds by the formation of an intermediate o-acylisourea that is highly reactive and short-lived in aqueous environments. The II attack of an amine nucleophile on the carbonyl group of this ester results in the loss an... 

However, for certain applications non-aqueous solvents have their advantages. Uni-univalent electrolytes dissolved at low to moderate concentrations in solvents with a relative permittivity larger than, approximately, 30 are completely dissociated into ions. Of the solvents on the List, methanol, glycols, glycerol, formic acid, ethylene and propylene carbonate, 4-butyrolactone, ethanolamine, 2-cyanopyridine, acetonitrile, nitromethane and -benzene, the amides, whether N-substituted or not, dimethyl sulfoxide, sulfolane, dimethyl sulfate, and hexamethyl phosphoramide have s > 30 at ambient conditions (Table 3.5). Most of these solvents have, indeed, been used in electrochemical processes. 

Although carboxylic as well as phosphoric esters are widely utilized in nature, phosphoric amides do not parallel their carboxylic counterpartners as the widespread biological struc -tures. This is most likely due to the low stability of the P(0)-N bond under acidic conditions a property resulting from the different bonding at the phosphoramidate function, relative to the carboxylic system. 

Since there is not much of conjugation between the P=0 group and the nitrogen in (2), 0 and N atoms can in principle behave as two independent basic centers. Medium effects upon the PMR shielding parameters of phosphoramidates demonstrated that in such a strong acid as trifluoromethanesulfonic amides (2) indeed exist, at least partly, as the 0 and N diprotonated species. 

As a consequence of the different electronic interactions within the phosphoramidate group, P-N bond cleavage in phosphoric amides, contrary to the behavior of analogous carboxylic compounds, is accelerated by the electron - donation at the nitrogen atom. 

An analogous propargylation can be attained with allenyl tributyl stannane however, this reaction is catalyzed by SiCU that is activated by a bisphosphor-amide catalyst. Note that in this case, the role of the Lewis basic phosphoramide is to increase the Lewis acidity of SiCU rather than to increase the nucleophilicity of the stannane [51b]. A discussion of these effects is provided in Section 7.4. 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

Phosphoramidates rearrange into a-aminophosphonates using chiral lithium amide bases e.g. 31 afforded aminophosphonate 86 from phosphoramidate 85 in 13% ee and 65% yield (Scheme 61)104. A slightly higher optical purity of 26% (55% yield) was obtained with chiral (R. R)-3 as base. The application of (—)-sparteine and BuLi gave 13% ee and a yield of 30%. A higher level of enantioselectivity was reached when a bisphosphonate (87) was reacted with (R,R) 3 in THF. Although the yield was only 30%, aminophosphonate 88 was obtained in 35% ee (Scheme 61). 

Lithium bis(trimethylsilyl)amide (2.50 mmol, 1.0 M in THF) was added dropwise to a solution of l,4-dimethoxy-2-hydroxymethylnaphthalene (2.29mmol) dissolved in 10 ml THF at —78°C. This was then added dropwise to a solution of bis(2-chloroethyl)phosphoramidic dichloride (2.75 mmol) dissolved in 20 ml THF, the reaction mixture stirred at —78°C 90 minutes, warmed to —20°C, and ammonia passed through the mixture 10 minutes. Thereafter, the mixture stirred an additional 10 minutes, 30 ml 2% HCl added, and then extracted 4 times with EtOAc. The combined organic layers were washed twice with saturated brine, dried, filtered, and evaporated. The mixture was purified by chromatography using methyl alcohol/EtOAc, 2 98, and the product isolated in 50% yield as a yellow oil, Rf = 0.59. H- and P-NMR data supplied. 

The beauty of this reaction lies in the fact that nearly all the facts needed to elucidate the mechanism are, in one way or another, in the products. Although the formation of II might seem somewhat tantalizing at first, a second glance will reveal that simply isomerization of I will suffice to account for it. A rather unusual isomerization, however, because activation of the a carbon of the ester as a nucleophile and introduction of foimaldehyde (from where ) at this carbon need justification. The first argument may be reformulated as the formation of an ester enolate, which is made possible by the advent of lithium amide superbases such as lithium diisopropyl amide (LDA) in aprotic tetrahydrofuran (THF)-hexamethyl-phosphoramide (HMPA) solvent mixtures. The participation of an ester enolate is emphasized by the formation of condensed diester IV. 

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