Mitsunobu reaction Triphenylphosphine-Diethyl azodicarboxylate

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,... 

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. 

Nucleophilic Attack at Other Atoms. The mechanism of reactions involving alcohols (or phenols) with the triphenylphosphine-diethyl azodicarboxylate (DAD) reagent (the Mitsunobu reaction) has now been reconsidered in the light of a number of spectroscopic and preparative studies in the past year. In an... 

The conversion of an alcohol to an amine can be achieved in a one-pot reaction the alcohol 1 is treated with hydrazoic azid (HN3), excess triphenylphosphine and diethyl azodicarboxylate (DEAD). The initial Mitsunobu product, the azide 14, further reacts with excess triphenylphosphine to give an iminophosphorane 15. Subsequent hydrolytic cleavage of 15 yields the amine—e.g. as hydrochloride 16 ... 

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-... 

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and diethyl azodicarboxylate.45 Hydrazoic acid, HN3, can also serve as the azide ion source under these conditions.46 These reactions are examples of the Mitsunobu reaction discussed earlier. 

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-... 

Tosylation with inversion.1 The reaction of a secondary alcohol with zinc tosylate, diethyl azodicarboxylate, and triphenylphosphine (Mitsunobu inversion, 5, 728) leads to the inverted tosylate in about 80-95% yield. Lithium tosylate is less effective. The reaction is sensitive to steric hindrance. 

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. 

Walden inversion, on the other hand, is observed in the reaction of alkanols with diethyl azodicarboxylate, triphenylphosphine and HN3 (c/. the Mitsunobu reaction).There is also some interest in the Pd-catalyzed transformation of allyl acetates into the corresponding azido derivatives. Primary amines can be generated in a one-pot procedure without isolation of these azides, by further treatment with PhsP and subsequent hydrolysis (Scheme 45). 

Grochowski, E., Hilton, B. D., Kupper, R. J., Michejda, C. J. Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates. J. Am. Chem. Soc. 1982,104, 6876-6877. 

The synthesis of 2,2-difluoro 3-amino-deoxystatine (74) is shown in Scheme 4. The key reaction is the stereospecific intramolecular Mitsunobu reaction (75). Condensation of the sodium carboxylate 7 with p-methoxyaniline gave the amide 8. Intramolecular cyclization with triphenylphosphine and diethyl azodicarboxylate afforded the P-lactam 9. Basic hydrolysis of the P-lactam ring gave the sodium salt of the protected difluoro 3-amino-deoxystatine 10. This proved useful in the preparation of peptide XII. 

Various solutions to the problem have been suggested. In a straightforward synthesis of aryl (3-D-mannopyranosides, 2,3 4,6-di-0-cyclohcxylidcnc-a-o-mannopyranose was treated with diethyl azodicarboxylate, triphenylphosphine, and a phenol in toluene (Mitsunobu reaction conditions) to give, after hydrolytic removal of the two cyclohexylidene groups, the (3-mannosidcs in good yield.37... 

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

In recent years, the Mitsunobu reaction has been studied extensively in solution and has found many useful applications. In an effort to overcome many of the problems associated with solution synthesis, the use of highly loaded triphenylphosphine polystyrene-derived resin represents a simple solution to the problem of purification. Thus, reaction of a series of alcohols of type 67 with carboxylic acids in the presence of diethyl azodicarboxylate (DEAD) and PS-PPhj in THF between 0°C and room temperature resulted in the clean formation of the expected esters of type 68. 5 Filtration through a plug of AljO, gave the essentially pure products in high yields (70-90%). 

A solid-phase preparation of benzoxazoles by the Mitsunobu reaction, suitable for the synthesis of a combinatorial library, has been described 2-aminophenol attached to a solid support is converted into the conesponding benzoxazoles by treatment with carboxylic acids in the presence of triphenylphosphine and diethyl azodicarboxylate in THF at room temperature <97TL6529>. Heating diacylated 2-aminophenols with toluene-p-sulfonic acid in boiling xylene gives high yields of benzoxazoles 61 <97T457>. 

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

The Mitsunobu reaction, discovered by Oyo Mitsunobu (1934-2003) in 1967, is one of the most important among modern synthetic reactions. It allows the replacement of the OH group of primary and secondary alcohols with a variety of nucleophiles, with clean inversion of stereochemistry and under mild conditions. The key reagents are triphenylphosphine and a dialkyl azodicarboxylate the latter is very often diethyl azodicarboxylate (DEAD). In addition, a key requirement is that the nucleophile should be acidic (for reasons you ll see below) carboxylic acids, phenols, thiols, imides, and activated carbon acids are all appropriate nucleophiles. 

Another interesting example of an inversion reaction is the Mitsunobu reaction, which displaces a hydroxyl with a carboxylate group. Reaction of a chiral alcohol with triphenylphosphine and diethyl azodicarboxylate (PhsP, DEAD) in the presence of a carboxylic acid results in the formation of a good leaving group followed by the Sn2 replacement of that group by the carboxylate nucleophile to give an ester product with an inverted stereochemistry. 

Reaction of adenosine with triphenylphosphine and diethyl azodicarboxylate gave the 2, 3 -phosphorane (105) and not the 3, 5 -phosphorane as previously reported (Mitsunobu et ai, Chem. letters, 1974, 1473). The structure was confirmed from H" and P n.m.r. measurements. With aradmo-adenosine the 2, 3 -/yxo-epoxide (106) was obtained in near quantitative yield xylo-adenosine also gave (106) but much more slowly and in only 60% yield. ... 

The Mitsunobu reaction involves the alkylation of a nucleophile with an alcohol in the presence of diethyl azodicarboxylate and triphenylphosphine. The Mitsunobu alkylation has now been applied to the alkylation of triphenylphosphonium tetra-fluoroborate (Scheme 61). ... 

Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. In A Review of the Mitsunobu Reaction, Georg Thieme Verlag Stuttgart, Germany, 1981 pp 1—28. 

The Mitsunobu reaction is another method frequently used to invert alcohol stereochemistry [for a review see Mitsunobu, O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products Synthesis 1981, 1-28]. An example is shown below. 

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