[fanxy]

Do someone know about  the suitable  condition of  this reaction?
i have tried to do this reaction in several conditions just as normal  pressure 、high pressure and 60℃.But the yield only reached about 10%.I'm really disturbed about it.Thank you !

[fanxy]

Could someone help me?
thank you!

[orgopete]

If you are getting 10%, that is better than I would have predicted.

Without know what you are trying to do, I might suggest an alternative method. Try the anion of benzenesulfonamide and additional base to reform the anion for the second alkylation.

[fanxy]

If you are getting 10%, that is better than I would have predicted.

Without know what you are trying to do, I might suggest an alternative method. Try the anion of benzenesulfonamide and additional base to reform the anion for the second alkylation.

I will try it.Use LinBu as the base!
Thank you very much!

[Dan]

We do double mesylate displacements like this routinely in our lab. We use benzylamine rather than ammonia. Typically we use benzylamine as the solvent as well and heat if required - you can get up to ~185 reflux for more hindered systems, but here there's a chance you're aminolyse your benzoyl group at high T so be careful. Once you have the tertiary amine in place you can cleave the N-Bn by catalytic hydrogenolysis to give your desired pyrrolidine.

Alternatively you could try triflate rather than mesylate and run the reaction at lower T. You'd need to watch out for furan formation in the triflation step too, that's sometimes a problem. I closed a di-triflate to a [3.2.1] bicyclic system with 3 eq of benzylamine in THF, RT to 50 degrees, earlier this week in about 70% yield so it can certainly be done.

The benzenesulfonamide approach is good, the only potential issue may be cleaving the N-SO₂Ph without cleaving the benzoyl group. Depending on what you intend to do with this stuff it might not matter though.

[fanxy]

We do double mesylate displacements like this routinely in our lab. We use benzylamine rather than ammonia. Typically we use benzylamine as the solvent as well and heat if required - you can get up to ~185 reflux for more hindered systems, but here there's a chance you're aminolyse your benzoyl group at high T so be careful. Once you have the tertiary amine in place you can cleave the N-Bn by catalytic hydrogenolysis to give your desired pyrrolidine.

Alternatively you could try triflate rather than mesylate and run the reaction at lower T. You'd need to watch out for furan formation in the triflation step too, that's sometimes a problem. I closed a di-triflate to a [3.2.1] bicyclic system with 3 eq of benzylamine in THF, RT to 50 degrees, earlier this week in about 70% yield so it can certainly be done.

The benzenesulfonamide approach is good, the only potential issue may be cleaving the N-SO₂Ph without cleaving the benzoyl group. Depending on what you intend to do with this stuff it might not matter though.

Your suggestion is very helpful!Thank you very much!

I have tried using benzylamine as the solvent at 90 degrees,but I did not get the anticipative product.Maybe the protection group benzoyl was  attacked too.Shoud I try a lower temperature?
The Trifluoromethanesulphonyl chloride is too expensive to industrial production.

[Dan]

I have tried using benzylamine as the solvent at 90 degrees,but I did not get the anticipative product.Maybe the protection group benzoyl was  attacked too.Shoud I try a lower temperature?

You could do, it depends. How long did it take to get complete consumption of the starting material? If the reaction is fast at 90 you can settle for a longer reaction time at lower temperatures and perhaps save the benzoyl group - if that's the problem. You say you didn't get the anticipated product, but what product(s) did you isolate? Did you isolate any?

The Trifluoromethanesulphonyl chloride is too expensive to industrial production.

Yes it is quite expensive, especially if you buy it from Sigma. Fluorochem offer trifluoromethanesulfonic anhydride at the best price I've ever managed to find (in the UK), which is about 1/3 of what Sigma charge. Still waaay more expensive than MsCl though, it's true.

Anyway, could you use a different protecting group? It's difficult to suggest one without knowing the details of the whole synthesis - which I realise you may not be at liberty to give - but that may solve the problem, and could open up the sulfonamide strategy.

[orgopete]

When I suggested using a sulfonamide, I was anticipating that your basic amine would effect an O->N acyl transfer. I expected that would be a good reaction as it is intramolecular. Therefore I was looking for a way that the alkylation reaction could be accomplished without generating a basic amine. You might try the same strategy with a carboxamide with sodium hydride in DMF.