[kriggy]

Hello, Im trying to convert methyl ester into different amides. My problem right now is that if I hydrolyze it to acid I cant get it out of aq. phase because the product has COOH and pyridine present and my yields are under 50%. I can do the reaction somehow using 2eq of amine, CsCO3 in toluene but it takes a while (days) AND requires elevated temperatures that might not be compatible with the molecule (it is chiral and can racemize at elevated temperature, we dont know at what temperature because I wasnt able (yet) to fully separate the enantiomers). Anyway, I was thinking that I could make the amine more nucleophilic by converting it into Li salt using BuLi but I was not able to find examples of lithium salts of primary amines, are the unstable? For that reason I was looking into some protecting group to make the amine secondary which should be more stable but all of the common protecting grooups seems to be labile to nucleophiles like BuLi...

Any ideas?

thank you

[rolnor]

You can use potassium cyanide as catalyst. If you make Li-salt it will be vey alkaline and then you get racemization.

[TheUnassuming]

I think any anionic salt of the amine will just increase racemization.  You could try AlMe3 - amine complexes (10.1021/jo00085a001).  The workup can be a bit messy like anytime you play with Al, but I've had good luck with it in the past.

[kriggy]

You can use potassium cyanide as catalyst. If you make Li-salt it will be vey alkaline and then you get racemization.

can you explain bit more the CN catalysis?

I didnt mention that but its axial chirality (atropoisomerism to be exact) and the only mechanism for racemization that seems plausible is simple rotation about the hindered bond.

[Babcock_Hall]

Do I assume correctly that the starting material has to be a methyl ester, and not some other ester?

[kriggy]

Do I assume correctly that the starting material has to be a methyl ester, and not some other ester?

Not really but I have the chiral resolution almost solved for methylester and im not sure if other ester will behave the same. But if you have any idea bring it on, if nothing else works for me then I could make the other ester as well

[rolnor]

You can heat the ester with the amine in a very concentrated solution, large excess of amine and add 10% potassium cyanide as catalyst. The AlMe3-method is maby more effective. If it is a aliphatic ester and an aliphatic amine it should not be so difficult if there is not a lot of steric hindrance.

[Babcock_Hall]

There are many others here with greater synthetic expertise than I have, but I have worked a little bit with 4-nitrophenylesters, turning them into amides involving the side-chain amino groups of BOC-ornithine and BOC-lysine, following the work of Folkers and collaborators in the early 1990s.  If I understand correctly, one advantage of the active ester approach when applied to peptide synthesis is less racemization (I don't have a citation, but I have heard others here say that this is true).  PNP-esters are slow to couple (days at room temperature in my experience), but one can follow the reaction by the release of the PNP anion spectrophotometrically.  Some people use pentafluorophenylesters, but I don't have any experience.

[wildfyr]

I have a lot of experience with pentafluorophenyyl esters and they are just about perfect. It's essentially a click reaction. Done in minutes to hours at RT, and they have very little hydrolysis. You can stir them in basic water and unless it's like pH 14 nothing will happen. Any tertiary amine or DMAP as a proton scavenger. High specific for amines over alcohols or thiols. It's slow with anilines but does go.

It's so reactive it will go quantitatively with amine terminated PEG.

The issue is that you have to go thru the acid chloride to get to the pentafluorophenyl ester.

[rolnor]

Kriggy wanted a one-pot procedure? If he has the acid available then standard peptide-coupling conditions is of course no problem.

[rolnor]

To estimate the racemization you can react the ester with a chiral amine and run NMR, the diastereomeres usually gives different spectra. If you have aliphatic amine and aliphatic ester it is possible you dont need to heat if you use large excess amine, also the Cs2CO3 is probably not helping the reaction?

[kriggy]

Kriggy wanted a one-pot procedure? If he has the acid available then standard peptide-coupling conditions is of course no problem.

I dont have the acid available, isolating it by ester hydrolysis is low yielding but its something Im also working on. THe hydrolysis is easy but getting it out of the mixture is not working well since I cant really acidify that much so its staying in aq. phase.

Im gonna look into the trimethylaluminium method, it looks most promising.

To estimate the racemization you can react the ester with a chiral amine and run NMR, the diastereomeres usually gives different spectra. If you have aliphatic amine and aliphatic ester it is possible you dont need to heat if you use large excess amine, also the Cs2CO3 is probably not helping the reaction?

Not sure what you mean by "helping the reaction" but the method with CsCO3 is reported prodecure.

Im not sure if the NMR method will work in this case because the structure of the compound doesnt allow for different shielding/deshielding effects (my student made similar compound and we saw only very small differences in chemical shifts that didnt allow for correct integration etc..

To sum it up:
a) getting the acid is not easy but I think I could make it work (isolation problem) then its walk in a park
b) direct amidation of ester would be best if its mild enough (Me3Al method seems like it)
c) getting different ester (pentaflorophenol or whatever) is doable but might require new set of chiral resolution (damn I wish we still had the prep. scale SFC with chiral collumns)

[rolnor]

What I am thinking about Cs2CO3 is that its not basic enough to pic a proton from the amine but att higher temp its basic enough to cause racemization. I am wrong since its a publisched procedure.

[wildfyr]

No way cesium carbonate can deprotonate an amine. Prove it to me and I still won't believe you.

Cesium is so weird.

[kriggy]

What I am thinking about Cs2CO3 is that its not basic enough to pic a proton from the amine but att higher temp its basic enough to cause racemization. I am wrong since its a publisched procedure.

I dont think the role of CsCO3 is deprotonating the amine. Its probably proton scavenger after the nucleophilic attack on ester.