Mitsunobu reaction azadicarboxylates

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. 

The commercially available diethyl azadicarboxylate like reagents are listed below. DEAD (4) and DIAD (5) are by far the most frequently used. The methyl (6), benzyl (7) and terr-butyl (8) analogs of the most commonly used reagents are also known, but used much less frequently. Bis-(2,2,2-trichloroethyl)azadicarboxylate, another commercially available compound, has also been reported, but applications thereof appear to be very limited. ADDP, l,r-(azodicarbonyl)-dipiperidine (10), was first reported by Tsunoda. This reagent appears be useful for more difficult Mitsunobu reactions related reagents in which the piperidine moiety has been replaced by morpholine or A-methyl piperazine are also known. These reagents and the reduced hydrazine products thereof can often be precipitated out by the addition of hexanes to Ae reaction mixture additionally, treatment with mild acid can be useful in the removal of the A-methyl piperidine reagent. 

The renaissance of solid supported reagents and parallel synthesis during the last fifteen years found numerous applications in the Mitsunobu reaction. Solid-supported triphenylphosphine and azadicarboxylate reagents were developed to aid in the purification of Mitsunobu reactions or help with difficult reactions. These reagents have become commercially available. In addition, important yield-limiting reactants were tethered to solid supports... 

An exception to the expected ester formation of a phenol and a carboxylic acid is found in the case of salicylaldehydes. Girard et al. found that salicylaldehydes (91) preferentially form hydrazones like 92 when DEAD or related azadicarboxylates are employed in the Mitsunobu reaction. The hydrazone formation occurs with or without a carboxylic acid coupling partner. If DEAD is used during the reaction, the neighboring alcohol is protected as the boc ester during the reaction. This presiunably occurs through Boc transfer from DEAD via a tetrahedral intermediate. The subsequent hydrazone formation can then proceed via a concerted or nonconcerted reaetion with the reactive triphenylphosphonium boc hydrazide species that is formed after the collapse of the tetrahedral intermediate. 

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