Advances in the Mitsunobu Reaction: An Excellent Organic Protocol with Versatile Applications

Abstract

The beginning of 1970’s may well be regarded as turning point in the area of organic synthesis when an efficient and straight forward strategy for the reaction of primary and/or secondary alcohols with variety of nucleophiles in the presence of triphenylphosphine and azodicarboxylate reagent was discovered by O. Mitsunobu and since then rapid progress has been made in understanding and applying the Mitsunobu reaction for various derivatization reactions. Due to versatile applications and mild reaction conditions associated with the said strategy, the Mitsunobu reaction has received much attention in the last almost fifty years and has been well reported. The basic objective of this review is to pay attention on the recent advances and applications of the Mitsunobu reaction particularly in last decade. The attention has also been paid to describe various modifications which have been explored in the traditional Mitsunobu reaction by substituting P (III) reagents or azodicarboxylate reagents with other suitable reagents or else using an organocatalyst with the objective to improve upon the traditional Mitsunobu reaction. In the present review we wish to report the major advancements achieved in last few years which are likely to be beneficial for the researchers across the globe.

Electrophilic Hydrazination of Cyclopropanols Using Azodicarboxylates via Copper(II) Catalysis: An Umpolung Strategy to Access β-Hydrazino Ketone Motifs

“…In the forward direction, cyclopropanol A6 and azodicarboxylate A7 were considered as synthetic equivalents for synthons A4 and A5 , respectively, with the exploitation of A6 as a β-homoenolate nucleophilic synthon that would be primed for addition to A7 as an electrophilic substrate. − We report herein a new Cu­(II)-catalyzed, electrophilic β-amination reaction of cyclopropanols using readily available azodicarboxylate or azodicarboxamide reagents to derive β-hydrazino ketone derivatives (Scheme , equation 4). Dialkyl azodicarboxylates, represented by DEAD and DIAD, are well known for their widespread application as activating agents in the Mitsunobu reaction, while they also find use as versatile reagents for oxidation/dehydrogenation (e.g., oxidative Ugi-type reaction), photocatalytic C–C bond cleavage, C–H bond amination, and α-amination of ketone, active methylene (e.g., cyanoacetate), and heterocyclic derivatives. − …”

Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral β-Amino Alcohols with 2-Pyridyl and 6-(2,2′-Bipyridyl) Moieties

“…We decided to convert chiral amino alcohols into the corresponding diamines using nucleophilic displacement with an azide anion, followed by Staudinger reduction (Figure 1). In fact, our first attempts to substitute hydroxyl with azide under the Mitsunobu reaction conditions [11][12][13] suggested that aziridine intermediates could be involved. Thus, another pathway relied on the synthesis of aziridines and later subjecting them to the ring-opening reaction.…”

Atroposelective Total Synthesis of Darobactin A

“…Ultimately, displacement of the alcohol with 3-bromo-2-nitrophenol ( 7 ) under Mitsunobu conditions proved most effective. Through extensive screening (see inset table, step 7), it was revealed that the unusual combination of PMe 3 and TMAD − in toluene afforded 21 in 60% yield (500 mg scale). Historically such reagents have been employed for carbon-based nucleophiles; in this case, the use of these conditions led to increased reactivity with considerable suppression of byproduct formation .…”