N-phosphoramidates

Figure 14 Polypeptide phosphorylation by reaction with cyclic sodium trimetaphosphate. 0-phos-phoesterification of serine and N-phosphoramidation of lysine easily occur at alkaline pH.

Phosphonium hexafluorophosphate, benzotriazolyl-N-hydroxytris(dimethylamino)-in peptide synthesis, 5, 728 Phosphonium salts chromene synthesis from, 3, 753 reactions, 1, 531 Phosphonium salts, vinyl-in pyrrole synthesis, 4, 343 Phosphonium ylides in heterocyclic synthesis, 5, 165 Phosphoramide, triethylene-as pharmaceutical, 1, 157 Phosphoramide, triethylenethio-as pharmaceutical, 1, 157 Phosphorane, pentaphenyl-synthesis, 1, 532 Phosphoranes, 1, 527-537 Berry pseudorotation, 1, 529 bonding, 1, 528... 

The high reactivity of N-H bonds has also been exploited to produce N-F denvatives without significant substitution on neighbonng C-H bonds, Diethyl-phosphoramidates of ammonia, alkylammes, and a,polar solvents to produce difluoroamine [57], N,N-difluoroalkylamines, and a,to-bis(At,7V-difluoroamino)alkanes [52] Acetamide undergoes fluonnation to give modest yields of N,N difluoroacetatnide and acetyl fluonde when fluorinated... 

Applications of oxazaphospholidine-borane complexes, cyclic phosphoramides, compounds with N—P=0 function, and other P-heterocycles in enantio-selective catalysis 99SL377. 

Chloro- and A TV-dichloro-phosphoramidate esters (20) and (21) are readily prepared from the parent phosphoramidate by direct chlorination in mildly acidic solution but when R = Ph, the use of t-butyl hypochlorite is preferable, to avoid chlorination of the aromatic nucleus. These compounds behave as pseudohalogens, (21) reacting with olefinic compounds such as styrene to give (22), which is also formed by chlorination of the N-phosphorylaziridine (23). ... 

Phosphoramidate analogues of dideoxyribonucleoside phosphates (26) and trideoxyribonucleoside phosphates are acid labile and can be hydrolysed enzymically. Snake venom phosphodiesterase cleaves (26) to thymidine and 5 -deoxy-5 -aminothymidine (27 R = H). The latter presumably arises by spontaneous decomposition of the phosphoramidate (27 R = PO3H2) and P—O fission must have occurred during the initial hydrolysis. With acid or spleen phosphodiesterase, (26) gave Tp and (27 R = H), i.e. P—N fission occurred. 

The phosphoramide, Me(Et0)P(0) NEt P(0)(0Et)2, independently synthesised by the route shown, was obtained only on heating the phosphazene at 165—175 °C for several hours. P N.m.r. and i.r. spectroscopy confirmed these findings and were used to show that the formation of XCH2p(0)(OR) N=PR R 2 was never accompanied by isomerization. 

Diethyl N,N-dimethyl phosphoramidate 2404-03-7 Organic synthesis Specific uses not identified Tabun (GA) 0.90... 

The reaction of diethyl methylphosphonite (59) with methyl N-chlo-roacetimide has been studied.30 Besides the normal Arbuzov product (60) large amounts of dialkyl methylphosphonates (61) and (62) are formed, presumably as a result of initial halogen attack. Whether (60) is formed directly (N-attack) or via (63) has not yet been clarified. A simple method to prepare N,0,0 -trialkyl phosphoramid-... 

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. 

REDUCTION OF ALKYL HALIDES AND TOSYLATES WITH SODIUM CYANOBOROHYDRIDE IN HEXAMETHYL-PHOSPHORAMIDE (HMPA) A. 1-IODODECANE TO n—DECANE B. 1-DODECYL TOSYLATE TO n-DODECANE, 53, 107 REDUCTION OF KETONES BY USE OF TOSYLHYDRAZONE DERIVATIVES ANDROSTAN-17 0—OL, 52, 122 REDUCTIVE AMINATION WITH SO-... 

A series of N-allyl sulfamates, phosphoramides, and phosphorimidates was prepared to explore the possibility of O- N rearrangements via the intermediacy of the contact alkene radical cation/anion pair, followed by 5-exo-trigonal radical cyclizations (Fig. 4) [142],... 

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. 

The reaction between phosphoramidate anions and C02, resulting in P—N bond fission, was first reported in the early 1960s the fate of the phosphorus-containing moiety was not described clearly, nor were any conclusions reached as to the stereochemistry of the reaction. The reaction of the anions (96) and (97) with C02 and CS2... 

When the phosphoramidic difluoride (116) reacts with diols, alkanolamines, or diamines, the manner of ring closure is dependent on n in a way which is both novel, and, from the synthetic viewpoint, potentially useful, although for compounds for which n = 2 a mixture of products (117 R = F or MeaN) may result.88... 

Relatively low molecular weight polymers include R1R2P(0)(N=PR1Ra) n-PRxR2OH (R1, R2 included alkyl, aryl, and alkoxy)175 and phosphoramidic acids from the hydrolysis of (NPC12)W,178 the latter of which form hydrophobic materials. 

Alkyl and glycosyl isocyanates and isothiocyanates are produced in good yield under phase-transfer catalytic conditions using either conventional soluble catalysts or polymer-supported catalysts [32, 33]. Acyl isothiocyanates are obtained under similar conditions [34]. A-Aryl phosphoramidates are converted via their reaction with carbon disulphide under basic conditions into the corresponding aryl isothiocyanates, when the reaction is catalysed by tetra-n-butylammonium bromide [35]. 

Phosphoramidates are organophosphorus compounds containing a P-N bond. In recent years, innovative prodrug approaches have been developed based on the cleavage of the P-N bond, two examples of which are presented here. 

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

A few organophosphorus insecticides are also phosphoramidates, hydrolysis of the P-N bond being considered a route of detoxification. This is exemplified by the metabolism of acephate (9.82, Fig. 9.15), whose mechanisms of activation and detoxification have recently been re-examined in mice to better understand the relative innocuity of the compound in mammals and its selective toxicity in insects [156],... 

DIISOPROPYLAMINE DI-n-PROPYLAMINE n-HEXYLAMINE TRIETHYLAMINE 6-AHINOHEXANOL DIISOPROPANOLAMINE TRIETHANOLAMINE N-AMINOETHYL PIPERAZINE TRIETHYL PHOSPHATE HEXAMETHYLENEDIAHINE HEXAHETHYL PHOSPHORAMIDE TRIETHYLENE TETRAMINE HEXAMETHYLDISILOXANE... 

The first observed product is the hydroxo-N-bound phosphoramidate complex, although there are almost certainly other intermediates. Both ester hydrolysis (to nitrophenolate ion) and transfer of a phosphate residue from O to N occur. An acceleration of at least 10 fold can be assessed for both processes, compared with the reaction of the uncoordinated ester with NH3 or 0H ion. The O to N transfer is a general biochemical occurrence, e.g. creatine kinase uses and creatine to transform ATP to ADP and form creatine... 

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