Triphenylphosphine diethyl azodicarboxylate

Physical Data see Triphenylphosphine and Diethyl Azodicar-boxy late. 

Handling, Storage, and Precautions all reagents and solvents must be anhydrous. In general, the Mitsunobu betaine (1) is generated in situ from the phosphine and the azodicarboxylate however, in some cases it is essential to preform the betaine. The betaine is an unstable, colorless, crystalline solid, rapidly hydrolyzed on contact with moisture. It can be crystallized from dry THE or CHCb/hexane. 

The Mitsunobu Reaction. A mixture of triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD) is generally used however, diisopropyl azodicarboxylate (DIAD) is cheaper and works just as well. The overall reaction enables the replacement of the hydroxyl group of an alcohol by a nucleophile X (eq 1). 

Without acidic components, IV-alkylhydrazinedicarboxylates (4) can be formed. NMR studies of the reaction of alcohols with DEAD and TPP in the absence of acidic components have revealed that the key intermediate is the pentavalent dialkoxyphos-phorane (5). In the presence of an acidic component, phospho-rane intermediates are present in equilibrium with the oxyphos-phonium salt (3).  

The combination of DEAD and TPP has been utilized most often as the condensation reaction system, but dimethyl, diisopropyl, and di-r-butyl azodicarboxylates (6) can also be used instead of DEAD the azodicarboxamide (7) has been used as well. Triphenylphosphine can be substituted by a variety of trivalent phosphorus compounds, including substituted triarylphosphines and trialky Iphosphines.  

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A very mild procedure for converting alcohols to iodides uses triphenylphosphine, diethyl azodicarboxylate (DEAD), and methyl iodide.24 This reaction occurs... 

Wang resin was purchased from Advanced ChemTech (1% DVB, 0.70mmol/g substitution, 100-200 mash, Cat. SA5009). Anhydrous tetrahydrofuran (THF), A/A-dimcthyl-formamide (DMF), methanol, dichloromethane, pyridine, 1,1 -carbonyldiimidazole (CDI), piperazine, homopiperazine, trans-1,4-diaminocyclohexane, 4-(dimethylamino)pyridine (DMAP), succinic anhydride, diglycolic anhydride, 3-methyl-glutaric anhydride, 2-aminophenol, 2-amino-p-cresol, 2-amino-4-tert-butyl phenol, /V-methylmorpholine (NMM), triphenylphosphine, diethyl azodicarboxylate (DEAD), and trifluoroacetic acid (TFA) were purchased from Aldrich Chemical Company, Inc. and used without further purification. PyBOP was purchased from Novabiochem. 

The role of the diethyl azodicarboxylate is to activate the triphenylphosphine toward nucleophilic attack by the alcohol. In the course of the reaction, the N=N double bond is reduced. As will be discussed subsequently, this method is applicable for activation of alcohols to attack by other nucleophiles in addition to halide ions. The activation of alcohols to nucleophilic attack by the triphenylphosphine-diethyl azodicarboxylate combination is called the Mitsunobu reaction. 

Mitsunobu conditions [triphenylphosphine/diethyl azodicarboxylate (DEAD)]7 and triphenylphosphite methiochde [(PhO)3P+MeI ] or dihalides [(PhO)3P + XX-j8 have been successfully applied to the synthesis of halogeno sugars. 

INVERSION, OF ALCOHOLS Cesium propionate. Triphenylphosphine-Diethyl azodicarboxylate. 

P-Lactams.1 A biomimetic synthesis of /3-lactams from chiral amino acids such as L-serine has been developed by Mattingly and co-workers. The protected amino acid (1) is first converted into the O-alkyl or O-acyl hydroxamate (2), which undergoes cyclization to derivatives of l-hydroxy-2-azetidinones on treatment with triphenylphosphine-carbon tetrachloride. This cyclization is also possible with triphenylphosphine-diethyl azodicarboxylate.2 The final step involves reduction of the N—OH group with TiClj.3 The advantage of this method over that of Wasserman (9,428), which involves cyclization of /3-haloamides, is that a strong base such as NaH is not required. 

Isocyanides. Ugi et at.3 investigated the synthesis of isocyanides (2) by dehydration of N-monosubstituted formamides (1) with triphenylphosphine-diethyl azodicarboxylate. In the 11 cases investigated, no isocyanide could be obtained in six of them. In the... 

Conversion of alcohols into amines.2 The reaction of phthalimide (1) with various alcohols and triphenylphosphine-diethyl azodicarboxylate gives N-alkylphthalimides (2) in yields of 60-90%. Since they are converted into amines by treatment with hydrazine hydrate (1, 442), the reaction provides a means of converting alcohols into amines. 

Nucleophilic Attack at Other Atoms. A Lossen rearrangement occurs when aromatic hydroxamic acids are allowed to react with the triphenylphosphine-diethyl azodicarboxylate complex in the presence of ethanol, to give the hydroxamates (49). 

O-protective groups such as 11 has been successfully achieved without affecting these groups by dehydration with triphenylphosphine-diethyl azodicarboxylate-iodine a mixture of anomeric C-nucleosides (12) was usually produced [94CL265 95JAP(K)95/118268] (Scheme 4). 

Holzer and Plagens (97H309) (Scheme 24) studied the alkylation of pyrazol-3-ones 62 and of the tautomeric pyrazol-3-one 78a-d/pyrazol-5-ol 79a d mixtures by applying the Mitsunobu reaction [triphenylphosphine, diethyl azodicarboxylate (DEAD), alcohol, solvent]. The reactions were performed in various solvents. Using methanol as the alkylating agent the reaction of 62 in dichloromethane or THF,... 

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