Alcohols Mitsunobu reaction

Biocatalysts are being applied widely in the industry, including the preparation of carbon-carbon bonds. Stereoselective oxidation with biocatalysts is an area where chemistry will find it hard to compete. A need still exists for new catalysts to replace stoichiometric reagents, as in the reduction of an amide to an amine, amide formation, and substitution of an alcohol (Mitsunobu reaction) (258). In both arenas of catalysis, the overall goal for green chemistry and stereoselectivity must be carbon-hydrogen bond activation. 

Inversion of configuration (cf Epimerization) of alcohols (Mitsunobu reaction), 160-161, 286 of ally lie acetates with Pd, 27, 164 of allylpalladium with d-synthons, 27, 264 of alkyl halides or sulfonates by 1,3-dithiane anions, 22 by organylcuprates, 36 by tetracarbonylferrate<2 -X 46-47 in triorganylborane rearr., 37-38 of glycosides with free 2-OH by DAST, 272 of glycosyl halides, 271 of oxiranes by 1-alkync anions, 64, 204 by enolate type anions, 63-64 by internal alcoholate addition, 265 Inversion-esterification of alcohols, 160-161, 286 Inverted DNA , 345-346 Iodide, hydrogen porphyrin synthesis with, 255 Iodine = diiodine (Ij) ... 

The Mitsunobu reaction is used to convert an alcohol and an acid into an ester by the formation of an activated alcohol (Ph3P, diethyl diazodicar-boxylate), which then undergoes displacement with inversion by the carboxylate. Although this reaction works very well, it suffers from the fact that large quantities of by-products are produced, which generally require removal by chromatography. 

Primary alcohols may be phosphorylated by use of the Mitsunobu reaction (Ph, , DEAD, HBF4, Pyr). Of several salts examined, the potassium salt of the phosphate was the best. 

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

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 ... 

Suitable starting materials for the Mitsunobu reaction are primary and secondary alcohols. Tertiary alcohols are less suitable since these are bad substrates for a SN2-mechanism. 

The Mitsunobu reaction was applied to the synthesis of pyrrolo[l,2-d [, 2,4]triazines from pyrrole derivative 71. Thus reduction of 71 gave alcohol 72, which on treatment with diethylazodicarboxylate and triphenyl phosphine gave 74 via the open chain intermediate 73. Hydrolysis of 74 gave 75 (84AG517) (Scheme 18). 

The Mitsunobu reaction was also applied to the synthesis of [ 1,2,4]triaz-ino[4,5-n]indoles (84AG517). Thus, reaction of the 2-acylindoles 127 with sodium borohydride in methanol or with lithium aluminium hydride in tetrahydrofuran gave the corresponding alcohols 128. Their cyclization with diethyl azodicarboxylate in the presence of triphenyl-phosphine gave the triazinoindoles 129. Acid treatment of the latter afforded 130 (Scheme 30). 

A Mitsunobu reaction for sterically hindered alcohols Qg% Tsudoda. T. Yamamiya, Y. Kawamura, Y. Ito, S. Tetrahedron Lett., 1995, 36, 2529... 

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. 

N-Alkylation of 2//-pyrido[l,2- ][ 1,3,5 tria/inc-2,4(3//)-dionc 81 was carried out with the alcohol 82 to obtain 83 under standard Mitsunobu reaction conditions (Equation 3) <2003JME3840>. 

The Mitsunobu reaction offers a powerful stereochemical transformation. This reaction is very efficient for inverting the configuration of chiral secondary alcohols since a clean SN2 process is generally observed ( Mitsunobu inversion ). Considering the fact that Mitsunobu chemistry is typically carried out at or below room temperature, high-temperature Mitsunobu reactions performed under microwave con-... 

The corresponding syn-compound can also be synthesized by simply inverting the stereochemistry of the hydroxyl group of the epoxy alcohol by the Mitsunobu reaction [54], Therefore, this method provides a simple and reliable method for the synthesis of any enantiomers and diastereomers of straight-chain 1,2-polyols. 

Weinges, K. Haremsa, S. Maurer, W., The Mitsunobu Reaction on Methyl Glycosides as Alcohol Component. Carbohydr. Res. 1987, 164, 453-458. 

A number of different reaction conditions were investigated for the Mitsunobu reaction and DIAD/PPh3 proved to be the most efficient combination of reagents. The dendronized support was then compared with the conventional TentaCel resin keeping the scaffold on the resin constant (glycine and 4-hydroxyphenylacetic acid) and employing four different alcohols. Much better yields were obtained... 

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