Sciencemadness Discussion Board

Amidation of cinnamic acid using CDMT

DrDevice - 2-7-2020 at 05:57

For some time I have been attempting to produce cinnamide from cinnamic acid, trying a host of methods, with very little success.
However, with the use of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and aqueous ammonia, I am now getting modest yields.

cinnamide reaction.gif - 12kB

From the literature, amidation of cinnamic acid is usually performed via oxalyl chloride then aqueous ammonia. CDMT is relatively straightforward to synthesize from inexpensive cyanuric acid - I have documented the method in another post - and the process is quick and easy.

The basic procedure is adapted from "Development of a Process for triazine-promoted amidation of carboxylic acids" (Rayle, Fellmeth, 1999), attached.


1.52g of cinnamic acid @ 148.16 (10.3mmol) and 1.8g CDMT @ 175.4 (10.3mmol) is stirred as a slurry in 20ml acetonitrile.

1.02 equiv of n-methyl morpholine (1.06g @ 101.15) is added drop wise over a few minutes. There is a mild temperature rise.

This is then magnetically stirred at room temperature. After about 30 minutes, the mixture thickens considerably. After 1 hour, the reaction mixture stirs more easily. At this time 2 equivalents of ammonia solution is added (1.8ml). I only roughly estimated the amount based on the approximately 25% ammonia solution I had on hand.

On addition of the ammonia, the solution becomes clear with a small amount of insoluble hydroxytriazine remaining. This is stirred for a further 10 minutes, after which the contents are poured into 200ml of water, and left in the refrigerator overnight.

The precipitated amide is filtered, washed with water and dried. Recrystalisation from chloroform gave 0.88g (6mmol @ 147.17) = 59%, as a white crystalline material.

MP 145 - 147C (lit 149C). TLC 1:1 EtOAc:hexane shows a single spot at Rf = 0.13.


The paper referenced also shows examples with straight cyanuric chloride, and aqueous inorganic bases. I had very limited success with anything other than CDMT and NMM as a base - I got a trace amount using NaOH.

Solvent choice doesn't seem too important. Another paper on s similar process suggests tetrahydrofuran.

I believe I am losing a lot in recrystalisation - I think I need a solvent mix.

TLC at the end of the addition of NMM but before addition of ammonia shows two distinct spots at Rf = 0.67 and 0.79. I'm guessing that only one of these goes on to react with the ammonia to form the amide, so maybe this explains the not-excellent yield?
Any suggestions on what the other product is (and how to suppress) welcome.

A small excess of ammonia doesn't seem to hurt. If insufficient is added, the solution is cloudy and TLC shows the two spots I mentioned above, together with the amide spot at 0.12. A few more drops of ammonia resolved that.

The paper shows reaction with sodium salts of the carboxylic acid. I intend to try this, as then the chloride should precipitate as sodium chloride thus need only 1 equiv of ammonia.

Attachment: rayle1999.pdf (50kB)
This file has been downloaded 441 times

mackolol - 2-7-2020 at 07:19

And what is cinnamamide useful for? Does it have any particular smell maybe?

kmno4 - 2-7-2020 at 14:34

What about classical amidation of methyl/ethyl ester of the acid ?
Does not it work ? In this particular case, there is no even need to prepare pure ester, its alcoholic solution is good enough.

Boffis - 3-7-2020 at 03:50

Is it actually necessary to convert the cyanuric chloride into CDMT first? You seem to be reducing the reactivity of the compound by 2/3 compared to the use of CYC to prepare acid chlorides. Could you not treat cinnamic acid with cyanuric chloride and then treat the acyl chloride with ammonia?

DrDevice - 6-7-2020 at 04:10

I've tried several approaches using ethyl and methyl esters (BTW, these smell quite nice - a "denser" cinnamon smell than cinnamic acid. The amide doesn't smell at all).

But no success via esters. Maybe it's procedural error on my part, but most of the amidation procedures are pretty straightforward. It just it doesn't seem to work :-(

I've also tried using the cyanuric chloride directly on the cinnamic acid - the paper I referenced has discussion on that. I also attempted via "Cyanuric chloride : a useful reagent for converting carboxylic acids into chlorides, esters, amides and peptides" (Venkataraman, Wagle, 1979) that uses triethylamine as a base. Nope, no joy there either.

DavidJR - 6-7-2020 at 04:15

Interesting that the methy/ethyl esters failed. Every time I have used that method for preparing amides it worked very well, even in the presence of chloride groups on the substrate that could potentially have alkylated
the ammonia. And it's easy and cheap too - basically just shake the ester with conc. ammonia solution.

By any chance did you try reacting cinnamoyl chloride, prepared from cinnamic acid and SOCl2 (or PCl5, or PCl3), with ammonia? Or using any peptide coupling reagents (carbodiimides etc)?

Or even just cooking the shit out of some ammonium cinnamate? Though I would not be surprised if that resulted in stinky polymerised tar...

[Edited on 6-7-2020 by DavidJR]

DrDevice - 6-7-2020 at 05:26

I haven't tried a "shaking the shit out of it" approach :-) I have tried refluxing it in conc. ammonia soln - maybe the heat was driving off the ammonia??

I have some ethyl cinnamate and now I know the TLC pattern I will see if the amide forms that way.

Cinnamoyl chloride seems to be the preferred method in the literature. But I don't have SOCl2, or PCl5, or PCl3. No cabodiimides either.

Right now I am preparing some ammonium cinnamate....

DavidJR - 6-7-2020 at 09:36

Quote: Originally posted by DrDevice  
I haven't tried a "shaking the shit out of it" approach :-) I have tried refluxing it in conc. ammonia soln - maybe the heat was driving off the ammonia??

Hmm, yeah I wouldn't be surprised if that was the case. Try using room temp ammonia. I've even used ice cold ammonia solution, for preparing chloroacetamide from ethyl chloroacetate. So long as it is kept cold, you don't get any significant reaction at Cl, but yet the ammonolysis of the ester still worked great.

kmno4 - 10-7-2020 at 11:27

I have tried recenly reaction of ethyl cinnamate (it was at hand) and NH3(aq) in MeOH, just to see what happens. Unfortunately, reaction performed around r.t. is very, very slow. After 3 days of stirring (two liquid layers, I added not too much MeOH), the vessel containg the mixture fell apart (tinny glass, bad shape of stir bar), only very small of tiny crystalline plates was detcted.
The most possibly this ester belongs to the class of unreactive (to ammonolysis) esters and harsher conditions are required (100 C, autoclave...) to force the reaction.

There are several other methods to make the amide, the cheapest seems to be reaction with urea. In the first step, around ~120 C, the acid reacts with urea giving N-acylated urea, which above ~160 C gives the amide (and HCNO turning to various products). Good for larger amounts of amide.
Possibly the N-acylated urea can be converted to the amide in some more "chemical" way than thermal decomposition, but simple hydrolysis may give cinnamic acid back (hard to predict for sure, depends on conditions, I think so).

In similar way, ammonium cinnamate can be converted to the amide (refluxing in toluene with boric acid and removing water), but it is not easy to prepare from water solutions and this salt can be prone to sublimation under these conditions....
But it is worth trying :P

Currently I cannot try these procedures personally, because I have few other projects started.

DrDevice - 13-7-2020 at 01:14

So it's not just me having no success with amidation of cinnamic acid or its esters. I too had ethyl cinnamate stirring with MeOH and aq ammonia with only the tiniest spot on the TLC after 3 days, the great majority of the ester untouched.

I have just about completed preparation of the ammonium cinnamate via action of ammonia gas on a methanol solution of cinnamic acid, and subsequent slow evaporation of the MeOH. Can you confirm the reference for the boric acid refluxing in toluene method for the amide - eg the Organic Synthesis paper "BORIC ACID CATALYZED AMIDE FORMATION FROM CARBOXYLIC ACIDS AND AMINES: N-BENZYL-4-PHENYLBUTYRAMIDE"?

I'll try that soon. I'm working on an approach using tosyl chloride also.

kmno4 - 13-7-2020 at 13:45

Yes, I confirm it, that is the paper. For slowly reacting reagents, o-xylene and larger amount of H3BO3 are better. However, lower temperature of reaction gives purer product.
For urea methode see for example "n-HEPTAMIDE" at Org Synt site.
For partial reaction with urea (N-acylated derivative), see for example "Arylboronic Acid-Catalyzed Direct Condensation of Carboxylic Acids with Ureas" (SYNLETT 2004, No. 8, pp 1355–1358). They use arylboronic acids, but I am sure that plain H3BO3 also works fine, as given in direct amide formation.
Just "arylboronic" is much modern and sounds better :)

kmno4 - 27-8-2020 at 11:12

I decided to repeat ammonolysis of ethyl cinnamate (25% ammonia aq and the ester (2,0 g)), but for a longer time (~ 30 days), at around 30 C, with occasional shaking/mixing.
The effect is about 0,6 g of white powder, soluble in EtOH, not soluble in water (at least at r.t.). It is also insoluble in petroleum ether and remaining ester can be separated from the amide by trituraton with this solvent. The product has bitter taste, as many other amides do.
So, simple ammonolysis realy works, but it requires longer time of reaction. Because each 10 C rise double reaction rate, at 100 C it may take hours, not days.

Pumukli - 28-8-2020 at 01:11

My experiences with aminolysis are based on benzoic acid ethyl ester reacting with aquaeous (40%) dimethylamine or some other secondary amine (anhydrous). The reaction with DMA solution is slow at room temp, reqires several days, even around 40 C it is slow. There is definitely some dimethyl-benzamide produced, but the yield is low, around 10-15% of theory. Hydrolysis is the preferred route in this case, unfortunately. With anhydrous (or almost anhydrous) amine and with boric acid catalysis at around 100 C the reaction is still slow, I refluxed the mixture for several days, but eventually the yield is much better. I used a Dean-Stark trap to collect ethanol from the reaction and it worked. I'm not sure about yield but the TLC seemed promising and the smell, well I could only smell the characteristic "DEET-like" smell, not the ester at all. (I still need to workup the mixture.) As a side note: I found it quite interesting, that dimethyl-benzamide, another longer chain dialkyl-benzamide and diethyl-m-toluamide (DEET) has very similar smell. (To be honest, I could not discriminate between them solely by the smell. But I'm not a mosquito.)

I know it is a cynnamic amide thread, and benzamides are not relevant at all. I just wanted to highlight the differences between the yields of the reaction with aquaeous and anhydrous amines.

DrDevice - 30-8-2020 at 17:41

Thanks everyone for the follow up. 30 days at room(-ish) temperature is quite slow...

At higher temperature, isn't there the problem of the ammonia boiling off? Or would that be done with eg a septum?

I attempted both the urea method and the ammonium cinnamate method. With urea, I obtained a black tar with no recognizable product, and got no reaction at all using ammonium cinnamate. I did only try both these the one time - I will try again sometime soon.

kmno4 - 26-12-2020 at 10:41

At last I have found some time for experiments with urea and cinnamic acid (=CA). At first, procedure from US2109941 patent was tested with CA. The patent looks too good to be true, at least I think so. Two pararel experiments were performed at the same time: one according to the patent (with 1,5 g CA), the second with addition of H3BO3. The final "product" is brownish, transparent resin in both cases and no tarry material is produced. This resin is soluble in many solvents, leaving produced amide as sediment. More details later.

In the meantime : a 110 years old note about the amide

cinamd.PNG - 61kB

[Edited on 27-12-2020 by kmno4]

kmno4 - 18-2-2021 at 02:02

Unfortunately, there is nothing interesting to report.
Heating of urea with CA at 130-160 C during several hours (tested even 24 h), gives more than ~50% unreacted CA (impure), some powdery high-melting white "something" and another low-melting something. After "purification" step (extracting with hot water), the white substance (bitter taste) melts rather sharply at ~220 C, so it is not desired amide.
What can it be ? I have found two papers* giving possible products of the raction CA+urea.
Desired cinnamamide was not observed at all in my experiments.

Some progress is obtained in ammonolysis of CA ester.
Chemical literature says that methyl esters are far more reactive in this reaction, so methyl cinnamate was tested. Indeed, it reacts about 10 times faster with ammonia than the ethyl ester does. About 15 days is needed to obtain more or less complete conversion of the methyl ester.

* for interested, by DOI:

[Edited on 19-2-2021 by kmno4]

njl - 18-2-2021 at 08:10

15 days with or without heating/agitation?

kmno4 - 18-2-2021 at 22:48

Quote: Originally posted by njl  
15 days with or without heating/agitation?

Room temperature, about ~7-fold excess of NH3 (as 25% aq sol.) and methyl cinnamate with MeOH (crude mixture from esterification of CA and MeOH + a little H2SO4). After mixing these solutions, emulsion is formed and soon small layer of methyl cinnamate is formed (at bottom). This later slowly (days) disappears and suspension of crystals (amide) slowly forms.
Unfortunately, ammonolysis, in this case, is not a matter of diffusion, so strirring or adding more co-solvent (also dioxane was tested) cannot change the rate of reaction. I think that at ~100 C it would take single hours to complete, but I do not have pressure vessel to check it. Possibly, performing the reaction in anhydrous conditions (ester+alcohol + NH3) with small amount of alkoxide (catalyst), the time of reaction would be also reduced.
The amide is also formed when NH3 is passed through molten CA at ~150 C, but it is more complicated than just keeping a mixture in closed bottle at r.t. :P

kmno4 - 1-4-2021 at 15:35

.... and cinnamamide for the last time.

Ethyl cinnamate (5 g), mixed with NH3 (aq) and dioxane, was kept in a closed bottle for a long time (slightly longer than 3 months).
The ester layer slowly (weeks) disappears and crystalline mass of amide is formed during long time.

It was filtered out, wshed with water, next pet. ether and dried.
About 1,7 g of rather large, white crystals is obtained. Foto is taken, but the crystals on the picture are slightly yellowish, I do not know why, in reality they are purely white.
cinnamde.PNG - 120kB
The filtrate was evaporated, noticeable odour of unreacted ester was still present. Obtained white powder was washed as above, after drying it gave additional 1,3 g of the amide.
The water washings contain some soluble salt, the most possibly it is just ammonia cinnamate (precipitate formation when acid is added)
Total yield is ~3 g - not bad, but the time of reaction is bad :P

In this way, my adventure with cinnnamamide is finished.

DrDevice - 3-4-2021 at 04:31

Thank you, kmno4, for the follow up. You have much more patience than me...

Coincidentally, I am just about to try amidation of some hydroxycinnamic acids with CDMT - coumaric acid, ferulic acid & sinapic acids.

My CDMT synthesis however is going wrong somewhere, with low yields compared to last time. I think my cyanuric chloride is a bit rubbish.

njl - 3-4-2021 at 14:08

Hey kmno4, if you have any ester and amine left at all would you mind trying the acid-catalyzed ester aminolysis described in the below paper? That is, same reaction conditions as your 3 month experiment but with catalytic acetic acid.