Preparation of (Cyanomethylene)trimethylphosphorane as a New Mitsunobu-Type Reagent.

Abstract

The Mitsunobu reaction is a very versatile method for the alkylation of various nucleophiles (HA) with alcohols (ROH) to give RA, utilizing the redox system of diethyl azodicarboxylate (DEAD)-triphenylphosphine (TPP) (Fig. 1). 1,2) 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 pK a lower than 11 for the reaction to proceed satisfactorily. If HA has a pK a higher than 11, the yield of RA is considerably lower, and with HA having a pK a 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) 3) and (cyano-methylene)trimethylphosphorane (CMMP) 4) 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 pK a of 11-23, such as N-methyltosylamide (3, pK a 11.7), 5,6) (cyanomethyl)phenylsulfone (4, pK a 12.0 in DMSO 7) ), 5,6) (methylthiomethyl)tolylsulfone (5, pK a 23.4 in DMSO 8) ), 5,6) benzyl phenyl sulfone (6a, pK a 23.4 in DMSO 9) ), 10) 3-[(phenylsulfonyl)methyl]pyridine (6b, pK a 16.7 in DMSO 9) ) 10) and geranyl phenyl sulfone (7, pK a 22.5 in DMSO 9) ).11)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 tributyl-or trimethylphosphine oxide can be attained by SiO 2 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 for...

Regioselective O-Alkylations of Indazolinone Using (Cyanomethylene)triphenylphosphorane

“…However, unlike traditional Mitsunobu reagents, trialkylphosphoranes are also thermally stable, 10 9 under standard conditions. pK a of nucleophile must be less then 11 to allow deprotonation step to occur CMMP is the most common trialkylphosphorane found in the literature, and it has been used successfully on indazoles, 11 activated methylenes, 12 and secondary amines.…”

A One-Step Synthesis of a Carbasugar Via a Wittig-Horner/Mitsunobu/Michael Triple-Tandem Mechanism

“…1 At room temperature this reaction did not occured. With CMMP as a Mitsunobu reagent the reaction can be carried out at high temperatures [11]. However, an increase in temperature would also facilitate the intramolecular Michael addition.…”

Total Synthesis of the Protein Phosphatase 2A Inhibitor Lactodehydrothyrsiferol

“…[25] The cyclic carbonate was converted into diol 27 through methanolysis, selective tosylation of the primary alcohol of the resulting triol by the Lilly protocol [32] (at which point a single diastereomer could be isolated), and reduction with NaBH 4 in warm HMPA. [33] The final ring closure was conducted by exposing 27 to the Tsunoda dehydration reagent (Me 3 P=C(H)CN), [34] a step that is analogous to the endgame of the synthesis of pseudodehydrothyrsiferol reported by Hioki et al [6] This led to the formation of 28 in 40% yield. Silyl ether cleavage by Bu 4 NF resulted in the isolation of 1 .…”