Amidation of cinnamic acid using CDMT

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.



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.

Procedure

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.

Notes

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)
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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??

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

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

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

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



[Edited on 27-12-2020 by kmno4]

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.

.... 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.

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

In this way, my adventure with cinnnamamide is finished.