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Issue 16, 2003
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The Hendrickson reagent and the Mitsunobu reaction: a mechanistic study

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The alkoxytriphenylphosphonium ion intermediate of the Mitsunobu reaction can be generated using the Hendrickson reagent, triphenylphosphonium anhydride trifluoromethanesulfonate, 1. Strangely, while the reagent 1 can be used in place of the Mitsunobu reagents (triphenylphosphine and a dialkylazodicarboxylate) for the esterification of primary alcohols, secondary alcohols such as menthol undergo elimination. Evidence is presented to show that this unexpected result is due to the presence of trialkylammonium triflate salts. Such salts lead to a dramatic decrease in the rate of esterification relative to competing elimination. The Mitsunobu esterification of menthol with p-nitrobenzoic acid was re-examined and the occurrence of elimination reported for the first time. The presence of traces of tetrabutylammonium triflate led to a dramatic reduction in the yield of inverted ester and a corresponding increase in the yield of anti elimination product 2-menthene. The mechanism of the Mitsunobu reaction is discussed in the light of the dramatic salt effect on both the rate and outcome of the reaction and the possible involvement of ion pair clustering. In contrast, use of the reagent 1 resulted in syn elimination to give a 1 ∶ 2 mixture of 2- and 3-menthenes. Finally, 1 and sodium azide can be used to convert a primary alcohol into an azide in high yield. There was no reaction under Mitsunobu conditions.

Graphical abstract: The Hendrickson reagent and the Mitsunobu reaction: a mechanistic study

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Publication details

The article was received on 14 May 2003, accepted on 25 Jun 2003 and first published on 15 Jul 2003

Article type: Paper
DOI: 10.1039/B305375J
Citation: Org. Biomol. Chem., 2003,1, 2958-2965

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    The Hendrickson reagent and the Mitsunobu reaction: a mechanistic study

    K. E. Elson, I. D. Jenkins and W. A. Loughlin, Org. Biomol. Chem., 2003, 1, 2958
    DOI: 10.1039/B305375J

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