MITSUNOBU Displacement

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

The enhanced acidity conferred upon / acyl phenols is sufficient for their participation in Mitsunobu displacements. Scheme 4.171 shows an example in which selective 0-benzyIation of the p-hydroxyl in the orcinol derivative 171 1 took place in preference to the o-hydroxyl.319... 

At this point, we investigated the reduction of the ketone to the phenethyl alcohol followed by Mitsunobu displacement as well as direct reductive amination. We were able to efficiently reduce the ketone racemically using NaBH4 in MeOH to alcohol 32. However, the subsequent Mitsunobu reaction proved problematic and no desired product was observed (Scheme 5.12). 

The mild reaction conditions for the displacement and hydrolysis steps combined with the spontaneous sigmatropic loss of dinitrogen allow the use of this chemistry in complex settings, including conjugated systems, to afford the desired reduction products (eq 4). This chemistry provides the desired reductive transposition products even in recalcitrant substrates for the invertive Mitsunobu displacement reaction (eq 5). 

Reductive Transposition of Allylic Alcohols. Similar to the synthesis of allenes from propargylic alcohols, the Mitsunobu displacement of allylic alcohols with IPNBSH followed by hydrolysis, diazene formation, and sigmatropic loss of dinitrogen provides reductively transposed alkenes. This methodology has proven effective for the reductive transposition of a variety of allylic alcohols (eq 2). The overall transformation provides the desired olefin with high selectivity in the formation of the irans-alkene (eq 3). ... 

Mitsunobu-type N-AIkylation of l,2,4-Dithiazolidine-3,5-dione (1). Despite its high acidity suggesting that it should be an excellent nucleophile in Mitsunobu displacement reactions of alcohols (cf. phthalimide. " ), the parent heterocycle 1 is degraded by the triphenylphosphine used in this process (see later). Similar stereoselective displacement reactions of alcohols with 1 can, however, be mediated using the readily prepared betaine reagent 7. ... 

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