Diphenyl 2-Oxo-3-oxazolinylphosphonate

[78605-38-6]  · C15H12NO5P  · Diphenyl 2-Oxo-3-oxazolinylphosphonate  · (MW 317.25)

(activation of carboxylic acids; formation of amides, b-lactams, and thiol esters; phosphorylation of alcohols)

Alternate Name: DPPOx.

Physical Data: colorless solid, mp 51 °C (n-hexane); bp 150-160 °C/0.03 mmHg.

Solubility: sol acetonitrile, THF, DMF, CH2Cl2.

Preparative Method: by reacting equimolar quantities of Diphenyl Phosphorochloridate and 2-oxazolone together with Triethylamine in CH2Cl2 at rt.1,2 The product is isolated in 96% yield by filtration of the triethylamine hydrochloride salts, concentration in vacuo below 30 °C, and chromatography of the residue on silica gel.

Analysis of Reagent Purity: 1H NMR: 6.74 (dd, J = 2.4 and 2.5 Hz, 1H), 6.81 (dd, J = 1.7 and 2.4 Hz, 1H), 7.32 (bs, 10H).

Handling, Storage, and Precautions: stable at rt, protected from moisture (over anhydrous silica gel), for several years. Complete hydrolysis occurs within 24 h in 50% aqueous THF at rt.

Activation of Carboxylic Acids.1,2

Reaction of diphenyl 2-oxo-3-oxazolinylphosphonate with alkyl, aryl, and unsaturated carboxylic acids yields the corresponding 3-acyl oxazolides under mild neutral conditions (eq 1). Alkoxycarbonyl-protected amino acids are amenable to the reaction conditions, except in cases where elimination is competitive, e.g. N-Cbz-serine. Sterically hindered 2,4,6-trimethylbenzoic acid failed to form the oxazolide, but instead gave the acid anhydride. 3-Acyl oxazolides of chiral acids, formed in this way, have been used in the synthesis of chiral amino alcohols,3 amino sugars,4 and hydroxy amino acids.5 The carboxyl group of the 3-acyl oxazolides is activated toward nucleophilic attack.

Amide Formation.1,2

Acyl oxazolides undergo facile aminolysis, leading to amides. Diphenyl 2-oxo-3-oxazolinylphosphonate reacts very slowly with amines. Thus the coupling can be achieved in one step by mixing an amine and a carboxylic acid in acetonitrile at rt with 1.2 equiv of DPPOx. This reaction has been successfully applied to peptide formation using Cbz and t-Boc protected amino acids and amino acid ethyl esters (eq 2) without racemization.

b-Lactam Formation.6

Treatment of b-amino carboxylic acids with diphenyl 2-oxo-3-oxazolinylphosphonate and triethylamine in refluxing acetonitrile (eq 3) gives good yields of monocyclic b-lactams (50-89%).

DPPOx was unsuccessful in cyclizing 2-thiazolidineacetic acid; however, the related tris(2-oxo-3-oxazolinyl)phosphine oxide (eq 4) gives the bicyclic b-lactam in 57% yield.

Thiol Ester Formation.7

Thiol esters are formed in 68-96% yield by reaction of thiols with carboxylic acids, DPPOx, and triethylamine in acetonitrile at rt (eq 5). Sterically hindered thiols require longer reaction times for comparable yields.

Phosphorylation of Alcohols.8

DPPOx reacts very sluggishly with alcohols at rt. However, the reaction is greatly accelerated by Cesium Fluoride and transition metal acetylacetone complexes to give mixed phosphates in good yields (eq 6). The catalytic ability of the complexes is in the activity order ZrIV > CeIII > ZnII > MnIII > MnII.

1. Kunieda, T.; Abe, Y.; Higuchi, T.; Hirobe, M. TL 1981, 22, 1257.
2. Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. T 1983, 39, 3253.
3. Kunieda, T.; Ishizuka, T.; Higuchi, T.; Hirobe, M. JOC 1988, 53, 3381.
4. Kunieda, T.; Abe, Y.; Iitaka, Y.; Hirobe, M. JOC 1982, 47, 4291.
5. Ishizuka, T.; Ishibuchi, S.; Kunieda, T. T 1993, 49, 1841.
6. Kunieda, T.; Nagamatsu, T.; Higuchi, T.; Hirobe, M. TL 1988, 29, 2203.
7. Kunieda, T.; Abe, Y.; Hirobe, M. CL 1981, 1427.
8. Nagamatsu, T.; Kunieda, T. TL 1987, 28, 2375.

Christopher D. Spilling

University of Missouri-St. Louis, MO, USA

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