4. N,S-Ketene acetals as substrates for aza-Claisen rearrangement


scheme 14

The substitution of the -OTBDMS with a -SMe group should have the following advantages:

a) higher stability of the N,S-ketene acetal due to the smaller electronegativity of the sulfur and

b) lower rearrangement temperature due to higher electron density in the rearrangement system

4.1. Synthesis of N-alkenyl-N-thiopropionyl-benzamides (16a-c)


scheme 15




Yield (%)










a) not improved yet

Thioimides 16a-c were synthesized starting from thioamides 15a-c [40-42] using a modification of the method reported by Weinstock [43]. Very important are the choice of the reaction temperature. The reaction mixture should be allowed to warm up slowly from 0°C to room temperature, otherwhise the sulfur will also be benzoylated. Amine bases like Et3N [44,45] or Et3N + DMAP [46], successfully used for the synthesis of other thioamides, were too reactive in our case and lead directly to the dibenzoylated product 17 in 92% yield (after addition of an additional equivalent of benzoyl chloride) (scheme 16). Unfortunately this compound showed no aza-Claisen reacitvity.


scheme 16

4.2. Synthesis of N-alkenyl-N-(1-methylsulfanyl-propenyl)-benzamides (14a-c)


scheme 17




Yield (%)










The synthesis of the compounds 14a-c was done without problems using the method of Gompper and Elser [47]. The reaction mixture was filtered through celite. Flash chromatography was impossible due to an isomerisation of the double bond to a mixture of the (Z) and (E) diastereoisomer. Therefore the product was used without further purification because it showed already a high purity of the N,S ketene acetal. Only the (Z) isomer was formed in analogy to the N,O ketene acetals.

4.3. Aza-Claisen rearrangement with compounds 14a-c


scheme 18



scheme 19



scheme 20

In contrast to our expectations the rearrangement temperature was not lower than with N,O-ketene silyl acetals, but almost 50 degrees higher. But the N,S ketene acetals showed higher stability than the N,O ketene acetals. Almost no degradation products were detected. The corresponding imides 4a,b,c were obtained without any problems in high yields (Scheme 18,19,20). In the case of the cyclohexenyl compound 14c it was impossible to isolate directly the rearranged product. A second product, which is not known yet, could not be separated by chromatography under the methods used so far. So we treated this mixture with SiO2/H2SO4 and obtained an overall yield of compound 4c for the rearrangement of 26%.

The high temperature needed for the rearrangement induces unfortunately the equilibration between the two observed rearrangement products. This could be proven when the rearrangement product 18 was heated for four hours at 180°C. The NMR-Spectra showed afterwards a mixture of the compounds 18 and 19 from 59:41 (Scheme 21):


scheme 21

In the case of allyl group this isomerisation has no detrimental side effect, but in the cases of crotyl and cyclohexenyl the diastereoselectivity is lost. Nevertheless it is very encouraging that the aza-Claisen rearrangement of the crotyl- and the cyclohexenyl-compounds 14b,c runs much better after the replacement of the oxygen by a sulfur atom.

We also tried to catalyze the aza-Claisen rearrangement of the N,S-ketene acetals. Unfortunately no product was observed with Pd(II). With Lewis acids only polymerization products were detected.

4.4. Change from benzoyl to benzyl


The exchange of the benzoyl protecting group by a benzyl group had no positive effect on the rearrangement. However the stability of the N,S-ketene acetals were considerably reduced.

Allyl-benzyl-(1-methylsulfonyl-propenyl)amine 24 was synthesized with sufficient purity from N-Allyl-N-benzyl-thiopropionamide. The relation of the Z/E-isomers were 2.5:1 (note: in the case of benzoyl we obtained only the Z isomer). 24 was directly used without any further purification for the aza-Claisen rearrangement (scheme 22):



scheme 22

Product 25 is the only rearranged product detected so far. The reaction mixture was directly introduced on a silicagel colomm. The acidity of the SiO2 was already sufficient to hydrolyze the rearrangement product. Besides small amounts of hydrolyzed starting material two other reaction products were isolated which are not identified yet.

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