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N,O- and N,S-Ketene Acetals as Substrates for Aza-Claisen Rearrangement


Klaus Neuschütz, Jimena Fernandez, Jean-Mary Simone and Reinhard Neier*

Department of Chemistry, University of Neuchâtel, CH-2000 Neuchâtel , (Switzerland)
______Klaus Neuschütz and Reinhard Neier______



Table of contents



1. Introduction

Tandem reactions are offering many advantages compared to a step-wise procedure: several reactions can be combined in one reaction step, shortening the synthetic plan considerably. At least one purification step can be avoided and therefore the losses associated with each purification can be minimized. Unstable intermediates occuring during a tandem reaction must not be isolated, which allows also to minimize the losses.

The combination of two electrocyclic reactions with their high stereocontrol and their synthetic utility leads to interesting tandem processes [1]. In our group the combination of a Diels-Alder reaction with an [3,3]-sigmatropic rearrangement has been studied. Diels-Alder and sigmatropic rearrangements show highly ordered transition states. Therefore the Diels-Alder / sigmatropic rearrangement tandem process combines high stereocontrol with shortened synthetic plan. We already reported the application of such a tandem reaction on the synthesis of iboga skeleton [2] (scheme 1).


scheme 1

To improve the synthetic utility of our initial tandem process we modified the system so that a new C-C bond is formed in the [3,3]-sigmatropic shift [3,4]. In our first trial we observed instead of the desired sequence Diels-Alder / [3,3]-sigmatropic rearrangement a new, unexpected Diels-Alder / intramolecular acylation tandem reaction occuring in good yields (scheme 2).


scheme 2

If the iso-propyl substituent on nitrogen is replaced by a benzyl group a different behavior is observed. Using acryloyl chloride no reaction was observed. Only with maleic acid anhydride 38 % of the Diels-Alder product could be isolated - but no tandem product. These observation indicates that the acylation step needs special reaction conditions [5]. In contrast to the N,O-ketene acetal the N-butadienyl-N-benzyl-propionylamide showed Diels-Alder reactivity with acryloyl chloride. This peculiarity is difficult to understand invoking only the electronic influence of the functional group attached to the butadiene.

In view of these results the following questions were asked:

1. Can the Diels-Alder reactivity be improved?

2. Can the acylation be suppressed?

3. What are the reaction conditions for the aza-Claisen rearrangement?

We choose to replace the benzyl protecting group on nitrogen by a benzoyl group.

The benzoyl protexting group should improve the stability to the N,O-ketene acetals. This protecting group should also be much easier to remove after the tandem reaction. We decided to test first the conditions necessary to do the aza-Claisen rearrangement. The following questions should be answered:

1. Which are the conditions for thermal rearrangement?

2. Is there a possibility to catalyze the reaction?

We synthesized therefore models for the Diels-Alder product and tested them in the aza-Claisen rearrangement under different conditions (scheme 3).


scheme 3


Besides the formation of the desired rearranged products some interesting and surprising side reactions could be observed.

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