Mitsunobu reaction, mechanism

Suitable starting materials for the Mitsunobu reaction are primary and secondary alcohols. Tertiary alcohols are less suitable since these are bad substrates for a SN2-mechanism. 

A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an retentive mechanism and an SnI racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An interrupted Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 l-Siloxy-l,5-diynes undergo a Brpnsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257... 

Sulfur chemistry is discussed in Chapter 46 all we will say here about the mechanisms of these reactions is that phosphorus is commonly used to remove oxygen and replace it by another element remember the Mitsunobu reaction ... 

In a process resembling the Mitsunobu reaction (Chapter 17), alcohols and acids can be coupled to give esters, even macrocyclic lactones as shown below. In contrast to the Mitsunobu reaction, the reaction leads to retention of stereochemistry at the alcohol. Propose a mechanism that explains the stereochemistry. Why is sulfur necessary here ... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

A review on the chemistry of thio derivatives of trivalent phosphorus acids which covers the literature to 1986, includes a section on pentaco-ordinate phosphorus compounds derived from addition to a-diketones and unsaturated systems activated to nucleophilic attack by electron withdrawing groups. Chemical bonding in hypervalent molecules has been discussed and qualitative bonding concepts developed to supersede the dsp and d sp models. A review on the mechanism and stereochemistry of the Wittig olefination reaction inevitably includes a discussion of the equilibrium between betaine and 1,2-oxaphosphetane intermediates. A correction has been published to reference 19 of Chapter 2 in SPR14, Vol.21, concerning the Mitsunobu Reaction. ... 

The Mitsunobu reaction has found wide use in the direct conversion of hydroxyl groups to other functionalities [12]. The mechanism for this reaction was previously discussed in Section 6.3.4 and illustrated in Scheme 6.8. 

The nature of the nucleophile is critical when considering the Mitsunobu reaction as a means of introducing amine functionalities. Because of the proton transfer components illustrated in the reaction mechanism, only acidic nitrogens can be introduced. The most common nitrogen nucleophiles include phthahmide, hydrazoic acid and zinc azide [62]. Once placed, phthahmides are easily converted to amines utihzing hydrazine [6]. Moreover, azides are easily reduced to amines under numerous conditions [32]. Schemes 6.32 and 6.33 illustrate the application of this chemistry to nucleosides [63] and pyranosides [64], respectively. 

An example of an alcohol activation method is the Mitsunobu reaction. This reaction is performed by slow addition of the seco-acid alcohol to a mixture of diethyl azodicarboxylate (DEAD) and PPhs in toluene or THF. In the mechanism, the key intermediate is an alkoxyphosphonium cation, which is formed by DEAD and PPhs in situ. The macrolactone is formed by an intramolecular Sn2 reaction of this intermediate via an attack of the carboxylate moiety and therefore the reaction proceeds with inversion of the configuration at C-co. 

Grochowski, E., Hilton, B. D., Kupper, R. J., Michejda, C. J. Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates. J. Am. Chem. Soc. 1982,104, 6876-6877. 

Kodaka, M., Tomohiro, T., Okuno, H. The mechanism of the Mitsunobu reaction and its application to carbon dioxide fixation. J. Chem. 

Watanabe, T., Gridnev, I. D., Imamoto, T. Synthesis of a new enantiomerically pure P-chiral phosphine and its use in probing the mechanism of the Mitsunobu reaction. Chirality 2000,12, 346-351. 

A few well-known and widely used reactions use a cocktail of several different reagents and proceed by multistep mechanisms that are not easily discerned by the beginning student. Two of these reactions, the Swem oxidation and the Mitsunobu reaction, are discussed here. You will find that faculty members enjoy asking graduate students to draw mechanisms for these particular reactions, so you should learn them well ... 

The first part of the mechanism of the Mitsunobu reaction involves addition of nucleophilic Ph3P to the electrophilic N in DEAD. (The alcohol could add to DEAD instead, but P is far more nucleophilic.) The addition is preceded by protonation of DEAD by the carboxylic acid. 

The mechanism of the Mitsunobu reaction of alcohols with phosphonic acids has been recently studied [ 109]. A typical Mitsunobu coupling reaction proceeds via Path A and it is generally recognized that the rate-determining step is the re-... 

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