Triphenylphosphine Mitsunobu reaction

Mitsunobu reaction Triphenylphosphine-Diethyl azodicar-boxylate, 44... 

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,... 

In summary the Mitsunobu reaction can be described as a condensation of an alcohol 1 and a nucleophile—NuH—11, where the reagent triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate reagent 12 is reduced to a hydrazine derivative 13 ... 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

A unique preparation of 2,3 5,6-di-O-isopropylidene-a-D-mannofuran-osyl fluoride (45) utilizing the Mitsunobu reaction [diethyl azodicarboxy-late (DEAD)-triphenylphosphine in the presence of EtjO BFi ii this case] has been reported (see Table 1). 

The role of the DEAD 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 is discussed later, this method is applicable for activation of alcohols to substitution by other nucleophiles in addition to halide ions. The activation of alcohols to nucleophilic attack by the triphenylphosphine-DEAD combination is called the Mitsunobu reaction.76... 

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and DEAD.76 Hydrazoic acid, HN3, can also serve as the azide ion source under these conditions.77 These reactions are examples of the Mitsunobu reaction. 

Triphenylphosphine reacts with peroxides to give intermediates that are related to those formed in the Mitsunobu reaction. The following reactions are examples ... 

The glycosylation based on the Mitsunobu reaction has been most commonly directed to the synthesis of O-aryl glycosides, a structural motif found in a variety of natural products [80-82], Early work by Grynkiewicz [83,84], among others [85-87], established the viability of triphenylphosphine and diethylazodicarboxylate to promote the glycosylation of phenol acceptors at ambient temperature. More recently, Roush and coworkers have discovered that the glycosylation performed well in the... 

A PEG-star supported triphenylphosphine analog (66) was synthesized and employed in Mitsunobu reactions. Four phenolethers were prepared within 3-18 h reaction time and 68-93% yield. Upon completion of the reactions, the formed polymer supported triphenylphosphine oxide was isolated by precipitation from diethyl ether in > 85% yield. The reagent could be recycled by means of alane reduction (73%). 

Iodination reagents combined with aryl phosphines and imidazole can also effect reductive conversion of diols to alkenes. One such combination is 2,4,5-triiodoimidazole, imidazole, and triphenylphosphine.215 These reagent combinations are believed to give oxyphosphonium intermediates which then serve as leaving groups, forming triphenylphosphine oxide as in the Mitsunobu reaction (see Section 3.2.4). The iodide serves as both a... 

In the case of the thiazolidinedioxides (38), the increased acidity of the cyclic sulfamide determines the reactivity. Metallation (NaH) occurs at N—H producing an anion which is readily alkylated <93TL4705>. Treatment with triphenylphosphine produces a stable betaine which can be used to couple alcohols and acids in a variant of the Mitsunobu reaction <94JOC2289>. 

An oxidizing agent. Useful for the dealkylation of amines and the conversion of pyrimidines to purines. It is most often associated with triphenylphosphine (TPP) in the Mitsunobu reaction. Examples ... 

Intermolecular and intramolecular nucleophilic substitution of an alcoholic hydroxy group by the triphenylphosphine/dialkyl azodicarboxylate redox system is widely used in the synthesis and transformation of natural products and is known in organic chemistry as the Mitsunobu reaction.1951 This reaction starts with formation of the zwitterionic phosphonium adduct 19 (Scheme 9) from triphenylphosphine and diethyl (or diisopropyl) azodicarbox-... 

Various p-amino thiols are synthesized from the corresponding P-amino alcohols 1 by activation of the hydroxy group to form a tosylate intermediate 2 and then conversion into a thioester 3 5 or direct thioacetylation of the hydroxy group of 1 using the Mitsunobu reaction with diisopropyl azodicarboxylate, triphenylphosphine, and thiolacetic acid as reagents (Scheme l). 6,7 The thioesters 3 are then hydrolyzed and the corresponding disulfide derivatives 4 are produced by iodine oxidation. 7 ... 

P-Lactams. The Mitsunobu reaction has been used to cyclize the protected peptide 1 to the / -lactam 2 in high yield. In practice, P(OC2H5)3 is superior to triphenylphosphine. The product is a protected form of (— )-3-aminocardicinic acid. 

Mitsunobu reactions have also been used for the cylization of 7-aminoalcohols toward azetidines. 7-Aminoalcohols 154, prepared from enantiopure ethynylaziridines, have been transformed into azetidines 155 upon treatment with dimethyl acetylenedicarboxylate and triphenylphosphine (Equation 35) <2001JOC1867>. N-Tosyl-substituted 7-aminoalcohols 156 yielded the corresponding 1-tosylazetidines 121 (Equation 36) with excellent diastereomeric (de = 99%) and enantiomeric excess (ee up to 99%) <2004EJ04471, 2005S3508>. 

The Mitsunobu reaction leads to the alkylation of alcohols with various nucleophiles or acids (HA) via a redox system, composed by diethylazadi-carboxylate (DEAD) and triphenylphosphine (TPP) (Figure 3.14). A limit in the application of Mitsunobu process is the pKa value of the acid counterpart, that must be usually smaller than 11 therefore, many improved redox systems have been developed in order to solve this problem. 

Next, triphenylphosphine in water was used for reduction to the primary amine. This process might remind you of the Mitsunobu reaction earlier in this chapter. 

One of the most widely used procedures for dehydrative coupling and cyclization reactions is the Mitsunobu reaction in which the components are treated with triphenylphosphine and diethyl azodicarboxylate (DEAD, EtOaC—N=N—COiEt). The overall equation for reaction of an alcohol 67 with an acid 68 to form the ester 69 is as shown and the active species is the zwitterionic... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

Side-chain anchoring of protected Asp or Glu to the Phacm resin 5 can take place with both low yields and substantial levels of epimerization at the a-carbon. The best route to overcome these problems is to use the corresponding cesium or zinc salts in conjunction with bromomethylbenzyl resins,or through a Mitsunobu reaction using triphenylphosphine and DEAD.[i 2]... 

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