TheMitsunobu Reaction

Abstract

Alkyl and aryl phosphites and phosphines react with compounds having weak heteroatom–heteroatom bonds, such as SS, OO, etc., and with azo compounds to form reactive phosphonium salts. These phosphonium salts in turn promote “redox” condensation reactions with compounds having active hydrogens. The condensation reaction of alcohols using the redox couple of a triaryl‐ or trialkylphosphine and a dialkyl azodicarboxylate has become known as the Mitsunobu reaction, based on his pioneering work in the late 1960s. The overall reaction is summarized, wherein the alcohol (R 1 OH) and acidic compound (H–Nu) are condensed to form product (R 1 –Nu), while triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate is reduced to the hydrazine. Although the typical redox combination is diethyl azodicarboxylate (DEAD) and triphenylphosphine, many other combinations have found selected use. The reaction is generally limited to primary and secondary alcohols, although tertiary alcohols react in a few intramolecular and intermolecular reactions. For secondary alcohols the reaction usually proceeds with clean inversion of stereochemistry. The acidic component of the reaction generally has an aqueous p K a < 15, with intramolecular reactions providing the exceptions. Examples of H–Nu include oxygen nucleophiles such as carboxylic acids and phenols; nitrogen nucleophiles such as imides, hydroxamates, and heterocycles; sulfur nucleophiles such as thiols and thioamides; and carbon nucleophiles such as β‐ketoesters. Major reviews of the Mitsunobu reaction were published in 1981 by Mitsunobu and in 1983 by Castro. The former review concentrated on reactions using DEAD/triphenylphosphine, while the latter review focused on reactions in which halogens replaced the hydroxy group using reagents such as triphenylphosphine/carbon tetrachloride, triphenyl phosphite/iodomethane, and triphenylphosphine/ N ‐halosuccinimide. Reactions involving the DEAD/triphenylphosphine redox system are the principal subject of this chapter, with emphasis on the literature between 1981 and 1988.

On the Synthesis and Reactivity of 4-(Oxiran-2-ylmethoxy)cinnoline: Targeting a Cinnoline Analogue of Propranolol

“…It should be mentioned that 1, which is exclusively present in the cinnolin-4(1H)-one form in polar organic solvents [4], exhibited a similar reaction behavior in methylation reactions using different conditions such as iodomethane/K 2 CO 3 , dimethyl sulfate, 4-toluenesolfonic acid methyl ester, methanol (in a Mitsunobu-type reaction [7]) [4]. Alternatively, it is known that 4-alkoxycinnolines are smoothly available from reaction of 4-chlorocinnoline (6) with appropriate sodium alkoxides [2].…”

Ionic Liquid Based Vilsmeier Reagent as a Substitute for Mitsunobu Reagent: Direct Conversion of Alcohols into Different Compounds under Ionic Liquid Conditions

“…The Mitsunobu reaction has found wide spread use in many fields because of its high versatility and extensive applicability (Mitsunobu, 1981;Hughes, 1992Hughes, , 1996. Since its introduction, the Mitsunobu reaction has been widely used for the re-functionalization of alcohols, as well as for inversion of hydroxyl group.…”

“…Considerable bulk of research has been done to expand the scope of Mitsunobu reaction and it has been used to achieve key organic transformations and major steps in different total synthesis schemes. The immense interest of chemists in this reaction is also evident from the several reviews have been published (Swamy, B. Kumar, Balaraman, & P. Kumar, 2009;Mitsunobu, 1981;Hughes, 1992 Mechanistically it is S N 2 type substitution powered by a redox process in which phosphorus is oxidized and the azo group is reduced. The key feature of this reaction involves the use of an organocatalyst diethylazodicarboxylateMitsunobu reaction give ester, alkyl azide, substituted imide, alkyl aryl ether, substituted sulfonamide and thioether respectively.…”

A Novel and highly selective conversion of alcohols, thiols, and silyl ethers to azides using the 2,4,6-trichloro[1,3,5]triazine/n-Bu4NN3 system

“…[5][6][7][8] Due to the advantageous and attractive strategy of the direct synthesis of azides from alcohols, some limited methods have been developed. Along this line, methods based on Mitsunobu conditions [7][8][9][10][11] are widely applied. These methods utilize reagents such as hydrazoic acid, diphenylphosphoryl azide, the bispyridine complex of zinc azide or the tetrabromocyclohexadienone/Ph 3 P system as the azide source/nucleophilic component.…”