[rolnor]

But the leavinggroup is an alcohol, there is no need to pic a proton?

[kriggy]

Then why is it there? because the reaction is not working without it... I think Cs coordinates to carbonyl O and then activates for the nucleophilic addition of the amine to form the tetrahedral imtermediate. If you use high excess of amine (like with aq. ammonia) then you dont need the base because the amine is base itself AND is in high excess that speeds up the reactio but if you use only 1-2 eq. of amine it might play a role..
I would say, without base, there is a proton transfer to form OH - NH which then has lower reactivity compared to negatively charged oxygen and NH as in the picture

[rolnor]

Interesting theory, my guess would be that the rate determining step is the attack of the amine on the carbonyl, the folloving steps are very fast, with or without the base Cs2CO3?
I dont think the Cs2CO3 would coordinate to the ester because Cs2CO3 allready contains thre oxygen atoms?
When using AlMe3 its another ball-game, its a hard Lewis-acid and Al has high affinity to oxygen.

[kriggy]

Yeah but the AlMe₃ procedure mentioned in this thread is not working for me. (Mixing AlMe3 with aniline.HCl then add to ester) I think I could just ghetto styl is and mix all together.
I would never thought its gonna be that difficult to make this reaction work.
Maybe even TiCl4 in place of AlMe3 could work

[rolnor]

Is it really the original procedure to use HCl-salt of the amine? Also if you have anilline it will be very difficult to get the amide from the ester, a aromatic amine is very unreactive. You need the free acid and use peptide-coupling conditions or acid chloride etc.

[TheUnassuming]

Ah, in your original post you said amine and I assumed aliphatic.  If you are trying to form aniline type amides, I don't think the Al - complex will work that well if at all. 

Have you tried to clip the ester to form the carboxylate, remove the solvent, dissolve/suspend in something like DMF and do the amide coupling directly (HATU ect)? It avoids the whole extracting a zwitterion problem all together.   I did something almost exactly the same a few weeks ago, with the exception that I used NMP as solvent and ended up using T3P to do the coupling.

Trying to go directly from the ester to the amide usually requires pushing, even more so with something as non-nucleophillic as an aniline. Even forming amides with relatively nucleophilic aliphatic amines from a methyl ester requires heating, which in the presence of base will almost certainly cause problems for your stereocenter.

[wildfyr]

If this is an aniline, I really think your conversion/yields are gonna be crap unless you can either A. heat the hell out of it or B. get to an activated ester scheme of some kind.

Since it sounds like A. is not an option due to the necessity of preserving a stereocenter, it sounds like B is all you've got.

[kriggy]

It doesnt have to be aniline but I thought it has higher sterical hinderance so why not. Im probably going to make some aliphatic as well, Im sorry for confusion, I didnt realize the reactivity differs THAT much.

I think the direct way is out of question now and Im gonna do it via hydrolysis-amidation step.

TheUnassuming: Kind of, I had few mg. but my reaction conditions were stupid so it didnt work (used DCC in DCM which obv, the acid salt is insoluble in) but Im going back to it, the options for that reaction is quite unlimited compared to direct amidation of ester

[wildfyr]

Steglich esterification (or amidation in this case I guess) in MeCN is a winner. A great trick is that DCU is poorly soluble in MeCN, so you can filter it off, reduce the MeCN, and recrystallize to remove all that highly annoying DCU salt. Better than diethyl ether in my opinion.

[kriggy]

Steglich esterification (or amidation in this case I guess) in MeCN is a winner. A great trick is that DCU is poorly soluble in MeCN, so you can filter it off, reduce the MeCN, and recrystallize to remove all that highly annoying DCU salt. Better than diethyl ether in my opinion.

Yeah, thats my way now. I tried making the amide using EDCl in DMF and worked like a charm but I think I lost some in HCl. workup so DCC in ACN seems like the way to go. I usually did them in DCM but since Im getting HCl. salt of my acid (weird right?) it doesnt dissolve and reaction is not working, but ACN or DMF are probably fine.

[Babcock_Hall]

wildfyr,

This is a tangential point, but one disadvantage of the 4-nitrophenolate ester approach that we found was efficiently removing the 4-nitrophenol (the peculiarities of our system might have made the job more difficult).  What about pentafluorophenylesters?

[wildfyr]

What would you like to know about it? Pentafluorophenol boils at 145°C 1 atm if you want to distill it off at reduced pressure, but I was working with polymers so I purified by precipitation. I would also expect bicarb extraction to do the job for either of those phenols.

PFPA esters react quantitatively with amines under any sort of basic conditions, and decently with alcohols in the presence of DMAP.

[OrganicDan96]

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.

you can make them by DCC coupling to carboxylic acid, i have done this before

[kriggy]

That could work but Im in trouble because during the ester hydrolysis OR amide coupling the compound completely racemize even at room temperature. So we have to changed tactics and we will separate the enantiomers by HPLC to get few mg for screening and then the best compound will be resolved.

[rolnor]

You could try to react the ester with hydrazine to get the hydrazide, this probably does not give razemisation. The hydrazide can be converted to a acyl azide with standard diazotation conditions, the azyl azide is very reactive and will give the amide upon treatment with amine, if needed DMAP can be used as catalyst.

https://en.m.wikipedia.org/wiki/Acyl_azide