Triphenylphosphine-Diethyl Azodicarboxylate ester formation

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%). 

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. 

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. 

Tosylate Formation with Inversion of Configuration. Alkyl tosylates can be formed directly from secondary alcohol functionality with retention of carbon stereochemistry by treatment withp-Toluenesulfonyl Chloride and Pyridine. However, conversion of an alcohol to the corresponding tosylate of opposite stereochemistry typically requires a minimum of three steps. For example, inversion of the stereocenter with benzoic acid under Mitsunobu reaction conditions, hydrolysis of the resulting ester, and finally conventional tosylation of the alcohol, provides an attractive route for this transformation. A similar route, the inversion of a secondary alcohol directly with p-TsOH, Diethyl Azodicarboxylate (DEAD), and Triphenylphosphine, does not produce the desired tosylate product. ... 

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