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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: kriggy on October 12, 2018, 05:15:42 AM

Title: Converting ester to amide in one pot
Post by: kriggy on October 12, 2018, 05:15:42 AM
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
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 12, 2018, 08:02:34 AM
You can use potassium cyanide as catalyst. If you make Li-salt it will be vey alkaline and then you get racemization.
Title: Re: Converting ester to amide in one pot
Post by: TheUnassuming on October 12, 2018, 09:51:33 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 12, 2018, 11:25:29 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: Babcock_Hall on October 12, 2018, 06:40:24 PM
Do I assume correctly that the starting material has to be a methyl ester, and not some other ester?
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 13, 2018, 05:18:53 AM
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
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 13, 2018, 06:13:48 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: Babcock_Hall on October 13, 2018, 11:01:10 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: wildfyr on October 13, 2018, 04:45:15 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 13, 2018, 04:52:28 PM
Kriggy wanted a one-pot procedure? If he has the acid available then standard peptide-coupling conditions is of course no problem.
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 13, 2018, 04:58:50 PM
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?
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 15, 2018, 04:49:53 AM
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)
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 15, 2018, 01:48:27 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: wildfyr on October 15, 2018, 07:46:30 PM
No way cesium carbonate can deprotonate an amine. Prove it to me and I still won't believe you.

Cesium is so weird.
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 16, 2018, 03:06:39 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 16, 2018, 05:17:16 AM
But the leavinggroup is an alcohol, there is no need to pic a proton?
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 17, 2018, 04:27:58 AM
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
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 17, 2018, 06:58:27 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 17, 2018, 07:31:23 AM
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
Title: Re: Converting ester to amide in one pot
Post by: rolnor on October 17, 2018, 12:43:50 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: TheUnassuming on October 17, 2018, 01:11:58 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: wildfyr on October 17, 2018, 01:37:36 PM
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.

Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 18, 2018, 01:28:41 AM
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
Title: Re: Converting ester to amide in one pot
Post by: wildfyr on October 18, 2018, 12:50:36 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: kriggy on October 20, 2018, 12:42:31 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: Babcock_Hall on October 20, 2018, 01:50:06 PM
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?
Title: Re: Converting ester to amide in one pot
Post by: wildfyr on October 26, 2018, 09:58:47 PM
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.
Title: Re: Converting ester to amide in one pot
Post by: OrganicDan96 on December 08, 2018, 04:05:43 PM
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
Title: Re: Converting ester to amide in one pot
Post by: kriggy on December 10, 2018, 05:23:04 AM
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.
Title: Re: Converting ester to amide in one pot
Post by: rolnor on December 10, 2018, 04:11:34 PM
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
Title: Re: Converting ester to amide in one pot
Post by: wildfyr on December 10, 2018, 04:42:48 PM
You gotta keep that thing pretty cold or else it will undergo spontaneous Curtius rearrangement
Title: Re: Converting ester to amide in one pot
Post by: kriggy on December 11, 2018, 03:57:50 AM
That looks pretty cool.
So, the acid azide is just heated with amine to get the amide?

ah I see, with heating I get the courtious rearangement, not that this wouldnt be interesting as well, to get some urea derivatives there
Title: Re: Converting ester to amide in one pot
Post by: rolnor on December 11, 2018, 05:59:30 AM
If you have some DMAP as catalyst you probably dont need heating.
Title: Re: Converting ester to amide in one pot
Post by: kriggy on January 07, 2019, 02:45:24 AM
Do you have some literature examples of the azide :rarrow: amide tranformation?
Title: Re: Converting ester to amide in one pot
Post by: rolnor on January 07, 2019, 05:19:46 AM
No, sorry. But this is an old reaction, also used i peptide synthesis, if you search on Scifinder etc. you will get hits.