[Seanlet]

Enamine ?

A friend has been asked to find a scalable route to make 1-(1,2-diphenylethyl)pyrrolidine and aromatic substituted of same (happily they haven't specified an isomer... but I'm guessing they might). He's been using 1,2-diphenylethanone and pyrrolidine with toluenesulfonic acid to make the enamine & is running it at reflux with a dean-stark apparatus for 48 hours (and since there are only staff there 12 hours a day, with setup & breakdown, it's taking a week.

I have been wondering if instead of toluenesulfonic acid and reflux, could he use toluenesulfonic anhydride as this would efficiently remove the water as it is formed and said water goes on to form 2 molecules of toluenesulfonic acid which would serve to shift the imine<->enamine towards the enamine?

I am hoping that it could be left running at room temperature with a stir-bar. It would still be in a fume-cupboard and I presume it would take longer, but if it means he can leave it running 24/7 then it makes up for it and to energy saving of refluxing for 48 hours is also worth considering.

Enamine Alternative

I have found a paper entitled 'Stereo- and Regioselective Gold-Catalyzed Hydroamination of Internal Alkynes with Dialkylamines'. This would use 1,2-diphenylethyne as the precursor but the catalyst is [AU(SMe2)Cl] (5 mol%) and the ligand is 2-(2-(di(adamantan-1-yl)phosphino)phenyl)morpholine (SMILES C1(C2OCCNC2)=C(P(C34CC5CC(C4)CC(C5)C3)C6(C7)CC(C8)CC7CC8C6)C=CC=C1) which look VERY expensive. It is the cornerstone of his thesis so He expects to have to perform 100s of very similar reactions just with different aromatic substitutions. This being the case, if bothe ligand & catalyst can be efficiently recovered then it would save him a LOT of time.

Reduction

He is following the textbook in using NaBH(OCOCH3)3 in GAA. At least I've pointed out to him that he can use NaBH4 as it becomes the triacetoxy on contact with GAA. His paper gives 4 options, NaBH(OCOCH3)3, NaBH4 (which I would have used) but also LiAlH4 (such fun!) and BH3 (!!!) I used 3 explanation marks because I think it's a mistake even suggesting borane to undergraduates.

I did briefly consider oxidative amination on stilbene but I cannot find any encouraging information on secondary amines, only ammonia and primary amines. Still, it would have certainly got him a very good mark if he succeeded in stilbene to 1-(1,2-diphenylethyl)pyrrolidine in a single step.



If anyone would like to add observations, suggestions, scorn and so forth - I would me most grateful.

[orgopete]

Let me start this off. For the first question, a rule of thumb is a reaction time halves for every 10^o temp increase. If you work backwards, the time doubles for every 10^o the temp is reduced.

Enamine reactions are enigmatic in that the amines are more basic than oxygens, yet protonation of an oxygen seems mechanistically plausible. I presume pTsOH is there to enable the dehydration step. If you add an anhydride, it will simply react with your secondary amine.

The problem is the reduced reactivity of an aryl ketone. I'd search the literature to see how this has been solved in the past.