Phosphine reagents, Mitsunobu reaction

Conventional reagents that cannot easily be removed by solid-phase extraction may be tagged in such a way that extraction by scavenger resins becomes possible. For example, for Mitsunobu reactions phosphines and azodicarboxylic acid derivatives of types 3 and 4... 

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... 

Bifunctional reagents have recently been used to facilitate separations in the Mitsunobu reaction.39 Mitsunobu products are often hard to separate from excess reagents and byproducts, including phosphines and phosphine oxides. The tagged phosphine 21 and azodicarboxylate 22 and the byproducts formed from these are converted to the carboxylic acid forms by treatment with trifluoroacetic acid (TFA) at the end of the reaction. The excess reagents and byproducts could then be captured on an ion exchange resin for convenient removal. 

Alternatively, alkyl aryl ethers can be prepared from support-bound aliphatic alcohols by Mitsunobu etherification with phenols (Table 7.13). In this variant of the Mit-sunobu reaction, the presence of residual methanol or ethanol is less critical than in the etherification of support-bound phenols, because no dialkyl ethers can be generated by the Mitsunobu reaction. For this reason, good results will also be obtained if the reaction mixture is allowed to warm upon mixing DEAD and the phosphine. Both triphenyl- and tributylphosphine can be used as the phosphine component. Tributyl-phosphine is a liquid and generally does not give rise to insoluble precipitates. This reagent must, however, be handled with care because it readily ignites in air when absorbed on paper. 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

This reaction is somewhat similar to the Mitsunobu Reaction, where the combination of a phosphine, a diazo compound as a coupling reagent, and a nucleophile are used to invert the stereochemistry of an alcohol or displace it. 

Curran, D. P., Dandapani, S. Fluorous nucleophilic substitution of alcohols and reagents for use therein, specifically, perfluoroalkyl-containing phosphines and azodicarboxylates as polyfluorinated reagents for the Mitsunobu reaction, 2002-US26045 2003016246, 2003 (University of Pittsburgh, USA). 

Mitsunobu reactions. An improved reagent pair consists of diphenyl(2-pyridyl)-phosphine and di-/-butyl azodicarboxylate. 

This reaction has been extensively modified, including the fixation of phosphine and dialkyl azodicarboxylate onto a polymer or fluorous reagent and the introduction of a basic moiety to a phenylphosphine. In addition, bis(2-(l-adamantyl)ethyl) azodicarboxylate (BadEAD), bis(l-adamantylmethyl) azodicarboxylate (BadMAD), bis(5-norbornen-2-ylmethyl) azodicarboxylate (DNAD), di-t rt-butyl azodicarboxylate (DBAD), fluorous azodicarboxylate (FDEAD), A,A,A, A -tetramethylazodicarboxamide (TMAD), and l,T-(azodicarbonyl)dipiperidine (ADDP), have also been developed for the Mitsunobu reaction. 

The Mitsunobu reaction, discovered by Mitsunobu in the late 1960s, has become one of the most widely used reactions in organic chemistry. The reaction has become the standard method for the inversion of secondary alcohols, the conversion of alcohols into amines and sulfides, and many other applications. New uses for this versatile reaction continue to be developed. The Mitsunobu reaction, due to its mild reaction conditions, has found wide application in total synthesis, and heterocyclic and medicinal chemistry. Since the Mitsunobu reaction has been extensively reviewed during the last thirty years, this chapter will focus primarily on applications of the Mitsunobu reaction during the last fifteen years. This review will cover recent examples for the various uses of the Mitsunobu reaction and introduce several new applications of the reaction. Recently developed phosphine and azadicarboxylate reagents will be covered as well. 

Catalytic Mitsunobu reactions in which substoichiometric amounts of phosphine or azodicarboxylate are used require much more work to find a workable solution. Some initial work in this area has been carried out by Toy and his group. Use of stoichiometric iodosobenzene diacetate as an oxidant to oxidize the reduced azodicarboxylate allowed the use of 10 mol% of DEAD or an equivalent reagent. How to use only catalytic amounts of phosphine in Mitsunobu reactions remains an unsolved problem. 

---