Chem. Pharm. Bull. 51(4) 474—476 (2003)

alkylation of various nucleophiles (HA) with alcohols (ROH) to give RA, utilizing the redox system of diethyl azodicarboxylate (DEAD)–triphenylphosphine (TPP) (Fig. 1). Without any prerequisite activation of the alcohol, it is a unique alkylation reaction and widely applied to various phases of organic synthesis. However, the reaction has a serious limitation; the acidic hydrogen in HA has to have pKa lower than 11 for the reaction to proceed satisfactorily. If HA has a pKa higher than 11, the yield of RA is considerably lower, and with HA having a pKa higher than 13, the desired reaction does not occur. In order to overcome these drawbacks and expand the versatility of the original Mitsunobu reaction, stabilized trialkylphosphoranes such as (cyanomethylene)tributylphosphorane (CMBP) and (cyano-methylene)trimethylphosphorane (CMMP) have been developed to replace the DEAD–TPP system. These new reagents were designed based on the structural similarity between the ylide 2 and the betaine 1 generated as an important intermediate in the Mitsunobu reaction (Fig. 2). The ylide 2, which is another resonance form of trialkylphosphorane, was expected to behave similarly with 1 towards a mixture of ROH and HA to yield RA along with the by-products, trialkylphosphine oxide and acetonitrile (Fig. 3). In fact, the trialkylphosphoranes, especially CMMP, mediate the Mitsunobu-type reactions of various kind of nucleophiles (Fig. 4) with pKa of 11—23, such as N-methyltosylamide (3, pKa 11.7), 5,6) (cyanomethyl)phenylsulfone (4, pKa 12.0 in DMSO), (methylthiomethyl)tolylsulfone (5, pKa 23.4 in DMSO), benzyl phenyl sulfone (6a, pKa 23.4 in DMSO), 3-[(phenylsulfonyl)methyl]pyridine (6b, pKa 16.7 in DMSO) and geranyl phenyl sulfone (7, pKa 22.5 in DMSO). The useful attributes of the new Mitsunobu reaction are as follows. 1) These reactions with secondary alcohols proceed with the complete Walden inversion of the stereochemistry at the carbinyl carbon. 2) The reaction of the DEAD–TPP redox system (the traditional Mitsunobu reaction) is not normally effective at higher temperature, whereas the reaction of CMBP and CMMP even at higher temperature can be carried out satisfactorily, because they are quite thermally stable although very sensitive to air and moisture. Furthermore, 3) in the traditional Mitsunobu reaction, one problem is the laborious purification of the product from dihydro-DEAD and triphenylphosphine oxide, whereas the use of the phosphoranes leads to an easy workup. Acetonitrile produced in place of dihydro-DEAD can be easily evaporated, and the removal of tributylor trimethylphosphine oxide can be attained by SiO2 column chromatography because of its high polarity. As an alternative workup for the reaction with CMMP, aqueous treatment of the reaction mixture is also quite effective because of the good aqueous solubility of trimethylphosphine oxide. Thus, the very high reactivity observed for the bond formation of C–N, C–C, and others renders these reagents and these procedures highly valuable and competitive from a synthetic point of view. Furthermore, it is a new substantial finding that the reagents can behave not only as a Wittig reagent but also as a Mitsunobu-type reagent. 474 Notes Chem. Pharm. Bull. 51(4) 474—476 (2003) Vol. 51, No. 4