The answer to your question comes from your country ! Please see the attached reference.

There is also another valuable attached reference. Good luck.

Thanks Dr. Nizar Matar. The first reference shows an amazed coupling yield but it is not an commercial product. It is hard for me to synthesize the coupling agent. I prefer a commercial one.

Dear Thinh , That is why I gave the second reference. I worked long time ago with DCC (commercially available) & it gave excellent results on synthetic polymers. There is now modified DCC-silica system but I do not have a good knowledge about it.

P.S. Why not contact one of the authors of the first reference ? They might have kept some of the coupling agent in the fridge of the lab. !

Hi Thinh

You can also carry out your reaction by using EDCL and HOBT in the solvent DCM at room temperature for 6 hours.

Cheers!

If you have no chiral centers next to your acid group, I would convert it to the acyl chloride and use this to add on the aniline.

Acyl chloride: DCM, (COCl)2, 1 drop DMF, 30min then some PhMe to azeotrope any excess oxalyl chloride that could remain and use the crude (can't purify acyl chlorides easily...)

Thanks all. It is lucky to get your recommendation. My monomer can only completely solute in highly polar solvent such as DMSO, DMF, DMAC. Do EDC and HOBT dissolve well in these solvent?

Hi Thinh,

HOBt - DMF solubility

http://www.sigmaaldrich.com/catalog/product/fluka/54804?lang=en®ion=IN

http://www.chemicalland21.com/lifescience/phar/HOBt.htm

EDCL-DMF solubility

http://www.actim.com/content/view/25/40/lang,en/

Cheers!

Hi..

I am also working on similar kind of couplings i.e. Anilines with COOH the best coupling is found when i use HBTU as a coupling agent and DIEA as a base under N2 atm at RT 4-5h only. first take acid, HBTU in Rbf, add DMF under N2 and add DIEA stirr it for 10min finally add ur aniline and keep it at rt 4-5hrs.

We have used PyBroP in acetonitrile under microwave irradiation with some good results.

http://www.sciencedirect.com/science/article/pii/S0045206811000976

The nucleophil aniline is very weak. Add 10 mol% DMAP together with DCC and stirr the reaction over night.

Years ago, I was working on the commercial scale amidation of a substituted aniline.  If you are doing lab scale only, you might not change your procedure, but if you scale up commercially, this is probably the best way to go.   

In my reaction, I used pivaloyl chloride, though I suspect the chemistry will work well with any acid chloride.  Ordinarily, one would do the chemistry in an organic solvent, but the amine on the aniline is so reactive with the acid chloride that I was able to run the reaction using water as a solvent, and get near quantitative yields.  The product separated out as a beautiful white crystalline material, which was easily isolated in a centrifuge bag, and the waste stream was salt water with a little bit of aniline in it. 

Since your monomer is soluble in DMSO, I'm guessing that water would be a fine solvent as well. 

I ran my chemistry on a 1000 gallon scale, and it worked right every time. 

If you try this on your reaction and it works well for you, please let me know.  As a patent attorney, it's always nice to know my knowledge of chemistry is still relevant.   

Hello David, your story astonished me because using water as a solvent will convert the acid chloride into carboxylic acid . The acid,RCOOH, will react with aniline giving "nice" crystals of anilinium salt. However, to get the amide, you have to decompose the salt by heating carefully & most probably the amide emerges colored (e.g. pale yellow).

Nizar:  I honestly didn't know it would work when I did the chemistry the first time.  We had used dichloromethane as solvent, but I'm a green chemist, so wanted to avoid that.  If you mix the aniline with the water, they are typically incompatible. 

On the lab scale, you would add the acid chloride dropwise,and the reaction with the amine is much faster than with water, so there was virtually no formation of free acid.  We scaled it up, and ran it on a 1000 gallon scale, routinely, without issue. 

The product obtained was the same as that obtained using dichloromethane as solvent, except that the purity was much higher, and product isolation much easier. 

This chemistry worked tremendously well, and was part of a commercial synthesis of a pharmaceutical agent for at least a ten year period of time.      

Regards - David

David, You did a very good order of addition (acid chloride to aniline-water mixture). As you know, the final aim of such reaction is an amide. However, the intermediate anilinium salt may be sold as well & indeed some like to purchase the salt instead of the amide due to its stability. I really liked what you did & thanks for the explanation. My regards, Nizar

You can try with HOAT in presence of DIPEA in DMF solvent,

HOAT can increase intramolcular basisity and HOBT is not, so less reactive amine can work with HOAT in better way.

you should try this reaction in microwave

Hello,

Activating your carboxylic acid as n-hydroxysuccinimide ester first may help ?

(use coupling agent to form the NHS-ester and add aniline in DMF/DIPEA  pH = 8-9).

Thanks all. Due to my lab condition, I'm now trying making amide following two method. The first is using EDC, HOBT and DIPEA. And the second is NHS-ester adding some DIPEA. Let's see the result.

Dear Thinh Nguyen,

I have some problems with this reaction,

please read: 

https://www.researchgate.net/publication/317239957_Efficient_total_synthesis_of_neocryptolepine_and_synthetic_access_to_6-methylquinindoline_from_a_common_intermediate

DOI: 10.1039/C7RA05349E

best 

daniel

Article Efficient total synthesis of neocryptolepine and synthetic a...

Hi Thinh Nguyen

Have you tried above said two method. The first is using EDC, HOBT and DIPEA. And the second is NHS-ester adding some DIPEA? Can u plz share the results?

Thanks

if you try the combinatin of Diisopropyl amide or DCC with DMAP in DCM as a solvent under nitrogen it might work..

Anilines are really bad nucleofiles especially when you have EWG groups in ortho or in para positions of the benzene ring.

For me the best solution has been the use of oxalyl chloride in dried DCM to convert the acid to chloride overnight.

The day after you evaporate DCM, add your Aniline in dried DCM and dried pyridine and let it mix for other 12h

I had troubles with EDC- Hobt methodology

Good luck!

What to do with some compounds that not easily solube?

I guess the aniline derivative may have EWG either in o or p position which is strongly deactivating. So, besides converting the carboxylic acid to the more reactive acid chloride, you could try using stronger base and better coupling agent such as DBU/pyBOP or the aza analague. This normally works for difficult coupling...

Good luck

Amide may not couple with aniline as both the compds . contain nucleophilic groups.

May I get a piece of information, please answer who are experienced:

Before adding the amine in amide coupling reaction, need stirring 30/20/60 minutes it depends on methods. But my question, after adding the amine in the reaction, is it need to continue stirring?