[Aerosolid]

Does someone here know how a condensation reaction of aniline with a an alpha-keto enamine proceeds? The reaction is performed in the total synthesis of "Minfiensine" by Wrobleski et. al., but I cant figure out the mechanism. It seems to me that there are two ways this type of compound (the alpha-keto enamine) should be able to react with the aniline nucleophile, but no matter if I do the 1,2 or the 1,4 addition, I don't get the product described in the synthesis..any help would be appreciated

[Dan]

Please post a link to the paper on the publisher's website (or give journal name, year and first page of the article so we can find it) so that we can see the reaction.

[Aerosolid]

The article specs are:

Dounay, A.; Humphreys, P.; Overman, L.; Wrobleski, A.: "Total Synthesis of the strychnos alkaloid (+)-Minfiensine: Tandem enantioselective intramolecular heck-iminium ion cyclization."; J. am. chem. soc. 2008, 130, 5368-5377.

It is the first reaction in "Scheme 2", between the protected anisidine and the keto-eneamine.

[Dan]

So 13 + 14  15?

For clarity, this reaction:

+   - pTSA

First, consider what the pTSA might protonate.

[Aerosolid]

Ok, I think I figured it out...first the carbonyl beta-carbon is protonated, effecting the generation of a morpholine iminium ion, which can be attacked by the aniline nitrogen. The addition is followed by protonation of the morpholine nitrogen, which is now ready to leave. When the morpholine leaves the enamine is reformed through the normal process, but now the aniline substituent in its place. That way the process proceeds without any interaction of the carbonyl group!!

Do you agree?

And thank you for your time  

[Dan]

Yes, protonation of the enamine C, generating an iminium (more reactive than the ketone), then transimination with aniline.

[Aerosolid]

Great. I got somewhat confused about the reversed reactivity of the alpha-beta unsaturated carbonyl. Thanks again