[26386-88-9] · C12H10N3O3P · Diphenyl Phosphorazidate · (MW 275.22)
(peptide synthesis;1 synthesis of a-aryl carboxylic acids;4 synthesis of thiol esters;7,8 stereospecific conversion of alcohols to azides;9 ring contraction of cycloalkanones;13 decarbonylation of aldehydes26)
Alternate Names: DPPA; O,O-diphenylphosphoryl azide.
Physical Data: bp 157 °C/0.17 mmHg; d 1.277 g cm-3; fp >110 °C.
Solubility: sol toluene, THF, DMF, t-butyl alcohol.
Form Supplied in: colorless liquid; commercially available in kilogram quantities.
Preparative Method: by the reaction of Diphenyl Phosphorochloridate with a slight excess of Sodium Azide in acetone at rt (85-90% yield).1
Purification: vacuum distillation (bath temp <200 °C, dec >200 °C)
Handling, Storage, and Precautions: handle and store under nitrogen. Refrigerate. Decomposes at >200 °C and may produce toxic fumes of phosphorus oxides and/or phosphine. Toxic, irritant. Harmful if swallowed, inhaled, or absorbed through the skin. Use in fume hood. Incompatible with oxidizing agents and acids. Hazardous combustion or decomposition products include carbon monoxide, carbon dioxide, and nitrogen oxides. Prolonged contact with moisture may produce explosive hydrogen azide (HN3).
Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in peptide synthesis,1-3 and as a versatile reagent in a wide array of organic transformations. DPPA has been successfully utilized in the synthesis of a-amino acids4 and a-aryl carboxylic acids;5,6 direct preparation of thiol esters from carboxylic acids and thiols;7,8 the stereospecific preparation of alkyl azides;9 and the phosphorylation of alcohols and amines.10 The application of DPPA in a modified Curtius11 reaction permits a simple one-step conversion of carboxylic acids to urethanes under mild reaction conditions. DPPA acts as a nitrene source,12 and can undergo 1,3-dipolar cycloaddition reactions.5,13 The Curtius degradation14 of carboxylic acids in the presence of t-butanol gives the Boc-protected amine directly (eq 1).
DPPA has been utilized in the synthesis of 1,4-dinitrocubane by Eaton and co-workers.15 Refluxing cubane-1,4-dicarboxylic acid with DPPA and Triethylamine in t-butanol forms the intermediate t-butyl carbamate in nearly quantitative yield. This method avoids the formation of the explosive diacyl azide.
Urethanes are readily prepared by refluxing equimolar mixtures of DPPA, a carboxylic acid, an alcohol, and triethylamine. The reaction involves transfer of the azide group from DPPA to the carboxylic acid. The resulting acyl azide subsequently undergoes a Curtius rearrangement. This reaction has been successfully applied in the area of peptide synthesis.1 The coupling of acylamino acids or peptides with amino acid esters or peptide esters in the presence of base proceeds in high yields without racemization, and is compatible with a variety of functional groups. The reaction of malonic acid half-esters results in the corresponding a-amino acid derivatives4 (eq 2). It should be noted that addition of the alcohol at the beginning of the reaction results in esterification.
Alkyl aryl ketones are converted into the corresponding a-aryl alkanoic acids4 via a three-step sequence. Yields of >90% are possible if the synthesis is carried out in a one-flask procedure. The sequence includes a 1,3-dipolar cycloaddition of DPPA to the corresponding enamines (eq 3). Although Thallium(III) Nitrate has also been used in similar oxidative rearrangements,16 the DPPA method exhibits higher functional specificity, uses less toxic reagents, and gives preparatively useful yields. Naproxen, a nonsterodial anti-inflammatory therapeutic, has been prepared by this route.6
Reaction of an alcohol with DPPA, Triphenylphosphine, and Diethyl Azodicarboxylate forms the corresponding azides in 60-90% yields.9 The stereospecific nature of this reaction permits the conversion of D5-sterols such as 3b-cholestanol exclusively to the 3a-cholestanyl azide in 75% yield. This synthesis is clearly superior to the alcohol -> tosylate -> azide route which is longer and also prone to competing elimination reactions.
DPPA undergoes 1,3-dipolar cycloadditions to the enamines of cyclic ketones.13 The resulting D2-triazolines, which are not isolated, undergo loss of nitrogen to form ring-contracted products, which, on hydrolysis, yield cycloalkanoic acids. In the case of six- to eight-membered cycloalkanones, overall yields as high as 75% have been reported (eq 4).
Reaction of organic azides with Grignard and lithium compounds gives 1,3-disubstituted triazenes,17 which are readily converted to amines by reductive18,19 or hydrolytic20,21 workup. These methods are limited to either the aromatic Grignard18,20 or lithium21 compounds, and have not been very successful with heteroaromatic organometallics. Aromatic and heteroaromatic organometallics (Grignard and lithium compounds) are aminated in good yields in a one-pot process by treatment with DPPA and reduction of the resulting phosphoryltriazenes with Sodium Bis(2-methoxyethoxy)aluminum Hydride (eq 5).22
The decarbonylation of primary aldehydes under catalytic conditions is difficult, requiring high temperatures or involving radical mechanisms;23 the rt decarbonylations24,25 using stoichiometric Chlorotris(triphenylphosphine)rhodium(I) have had limited practicality due to the high cost of the reagent. Recently, a high-yielding, rt decarbonylation of primary aldehydes using catalytic amounts (5 mol %) of Rh(PPh3)3Cl and stoichiometric amounts of DPPA, with minimal formation of alkene byproducts, has been developed26 (eq 6).
Macrocyclic lactams are conventionally prepared by the reaction of dicarboxylic acid chlorides with diamines, a method which is effective with simple acyl chlorides. Activation of the carboxylic groups in order to overcome the drawbacks of high dilution and the low yields and purity encountered with larger acyl chlorides has seen only limited success.27 The superior activating ability of DPPA has recently been demonstrated.28 The reactions of dicarboxylic acids and diamines in the presence of DPPA form macrobicyclic lactams in yields as high as 82%. By comparison, in a control experiment using conventional high-dilution techniques, the corresponding acyl chlorides cyclized with the diamine to form the lactam in only 24% yield.
DPPA has been used for the direct C-acylation of methyl isocyanoacetate with carboxylic acids to give 4-methoxycarbonyloxazoles.29 L-Daunosamine, the glycone component of anticancer anthracycline antibiotics, has been synthesized from L-lactic acid in 9 steps with a 24% overall yield,30 where a key step in the sequence is the direct C-acylation of methyl isocyanoacetate with the lithium salt of the lactate ester using diphenyl phosphorazidate (eq 7).
Albert V. Thomas
Abbott Laboratories, North Chicago, IL, USA