Mitsunobu reaction halogenation

The initial discovery route to analogs of crizotinib is shown in Scheme 1, and was designed to vary the nature of the aromatic moiety at a late stage in the synthesis. Initial borohydride reduction of the acetophenone generates the racemic alcohol, which is coupled to 3-hydroxy-2-nitropyridine through a Mitsunobu reaction. Nitro reduction followed by bromination introduces the halogen to the 5-position. Boc protection of the amino function enables Pd-mediated borylation to be employed to introduce the... 

Introduction of a halogen atom into the amine component is not possible, but an alternative solution is represented by the use of ethanolamines 26, performing the cyclization under Mitsunobu or Mitsunobu-like conditions to give ketopiperazines. These compounds have been observed as side products in reactions promoted by... 

A preformed complex of diethyl azodicarboxylate/PhsP activates primary and secondary alcohols sufficiently for SN2-type reactions with LiF (Scheme 33). This Mitsunobu procedure is a rare example of a reaction useful with all four halogens. 

Because (in part) of its expansion to include a variety of nucleophiles that allow for carbon-carbon, carbon-halogen, carbon-nitrogen, and carbon sulfur as well as carbon-oxygen bond formation and because (in part) of the variety of subtle changes that are employed to effect the desired overall reaction and because (in part) the changes can be carried out in one or more of the steps in the process, the overall technique has become known as the Mitsunobu protocol. 

As already noted, the amino group can affect displacement reactions on halogen (vide supra) and, in the presence of activating reagents (see, e.g., the Mitsunobu protocol, Chapter 8, Scheme 8.32 and this chapter. Scheme 10.23), can also displace oxygen. In that vein, it is worthwhile noting that P-aminoalcohols can be prepared by attack of amines on relatively unhindered epoxides (oxiranes) (Equation 10.59). 

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