Phosphorazidates

DIPHENYL PHOSPHORAZIDATE (Phosphorazidic acid, diphenyl ester)... 

The bath temperature should be kept below 2Q0°C to minimiie decomposition of diphenyl phosphorazidate. ... 

Diphenyl phosphorazidate is a colorless non-explosive oil that can be kept for a long time without decomposition if it is protected against light and moisture. 

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 crude enamlne (1) is dissolved in 20 mL of toluene, and the solution is transferred (Note 3) to a 100-mL, three-necked flask equipped with a magnetic stirring bar, 50-mL dropping funnel, reflux condenser protected with a calcium chloride tube, and a thermometer immersed in the solution. A solution of 13.2 g (0.048 mol) of diphenyl phosphorazidate (Note 4 uarntng) in 20 mL of toluene is added with stirring during 30 min di11e the reaction temperature is maintained at about 25°C. The mixture is stirred for 4 hr at 25 C and heated at reflux for 1 hr. The mixture is transferred to a 300-mL, round-bottomed flask and most of the toluene is removed under reduced pressure to yield 23.7 g of a reddish-brown oil, 2 (Note 5). 

Diphenyl phosphorazidate is prepared by the action of sodium azide... 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

The Grignard reagent prepared from chloromethyltrimethylsilane (30 mmol) and Mg (36 mg atom) in ether (20 ml) was added dropwise to diphenyl phosphorazidate (27 mmol) in ether (40 ml), keeping the temperature below 0°C. The reaction mixture was stirred for 2 hat 0 C, and then at ambient temperature for 3 h. It was then cooled to 0 °C, and ice-water was added. The mixture was filtered, and the solid was washed with ether. The combined ethereal extracts were washed with ice-water and dried. Careful concentration at <45 °C/atmospheric pressure, then distillation at... 

This reaction can be extended to secondary alcohols with the more reactive bis- 4-nitrophenyl)phosphorazidate.79... 

FIGURE 7.26 Reaction of diphenyl phosphorazidate (DPPA) with a carboxylate anion to give the acyl azide.90... 

Organolithium or Grignard compounds derived from aryl or heteroaryl halides react with diphenyl phosphorazidate to give labile phosphinoyltriazenes, which on reductive work-up with aluminium hydride afford good yields of aryl or heteroaryl amines (equation 7)34. 

Diphenyl phosphorazidate, obtained from either Dalichi Pure Chemicals Co., Ltd. or Aldrich Chemical Company, Inc., was purified by distillation under reduced pressure bp 134-136 C/0.2 nn. It can be easily prepared according to Org. Synth. 1984, 62, 187. 

Diphenyl phosphorszldate can be replaced with diethyl phosphorazidate in the above procedure. Use of other azides such as p-toluenesulfonyl azide, p-methoxybenzyloxycarbonyl azide, diphenylphosphinic azide, or diphenylthio-phosphinic azide is less satisfactory. No reaction occurs when trimethylsilyl azide, dimethylthiophosphinic azide, or alkaline azides are used, while decomposition of formed trimethylsilyldiazomethane seems to occur when... 

Another cycloamidation reagent which has found wide use is diphenyl phosphorazidate (DPPA)J9 In their synthesis of K-13 (9), Boger and co-workers used DPPA to form the 17-membered cyclic peptide 13 (Scheme 3) J4,5 ... 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

Diphenyl phosphorazidate, 222 Diphenyl phosphorochloridate, 223 Diphenylselenium bis(trifluoro)acetate, 223-224... 

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