Vanillyl acetamide is the simplest member of capsaicinoid family. Many hot and spicy compounds like capsaicin belong to this family of secondary
metabolites. These compounds can be accessed with relatively simple synthetic means and with the interesting (but relatively harmless) bioactive
profile they are ideal for amateur study.
Synthesis route was designed to work with easily obtainable materials and require no difficult purifications. Starting from vanillin is a obvious
choice as it provides the aromatic end with correct substitution. Installation of the necessary amine can be done with relatively simple modifications
to the aldehyde. Vanillin is treated with hydroxylamine to prepare the corresponding oxime in high yield. Affordable zinc reduction will lead to
desired vanillylamine, this reduction can also be carried out with H2/PdC or LAH. Vanillylamine can then be N-acetylated to yield the target molecule.
Changing acetic anhydride for longer chained acid chlorides gives access to other derivatives.
Scheme 1. Synthesis route
2 Experimental
2.1 Vanillin oxime
Hydroxylamine hydrochloride (1.00 g, 14.4 mmol) and sodium acetate trihydrate (3.58 g, 26.3 mmol) were dissolved in 15 ml of water. Vanillin (2.00 g,
13.1 mmol) was added and the mixture refluxed for 10 min. After cooling to RT formed crystals were vacuum filtered and washed with 2x 5 ml of cold
water. White crystals 1.82 g (76 %)
2.2 Vanillyl amine
Vanillyl oxime (1.00 g, 6.00 mmol) was dissolved in 10 ml of acetic acid. Solution was cooled to 15°C and zinc dust (1.57 g, 24.0 mmol) was added.
Stirred mixture was allowed to warm to RT over 3 hours. Excess zinc was filtered and filtrate carefully neutralized with ammonia. Formed solid was
vacuum filtered and washed with 2x 10ml cold water. Off-white powder 0.68 g (74 %)
Picture 1. Reduction proceeding
2.3 Vanillyl Acetamide
Vanillyl amine (0.50 g, 3.26 mmol) was dissolved in 5 ml of sat. NaHCO3(aq). Acetic anhydride (0.5 ml, 5.3 mmol) was added dropwise to the stirred
mixture. After 15 min the mixture was extracted with 4x 10 ml of chloroform. Organic extracts were combined, dried with sodium sulfate and the solvent
was evaporated. Thick syrup 0.165 g (26 %)
3. Discussion
This route gives an easy access to interesting molecules. Synthetic steps are well described in literature and starting materials reasonably
available. Biggest problem is the yield in the acetylation step as the final product is very soluble in both chloroform and water. This is not such a
big problem when the chain length is longer.
I would find it very interesting to apply this method for longer chained capsaicin derivatives as well. The necessary acid chlorides can be easily
bought or made from corresponding acids.
It should also be noted that the short-chain variants are not pungent nor irritant. With longer chains the final product has to be handled with utmost
care though!
4. References
Addison Ault, Techniques and Experiments for Organic Chemistry, 6th edition, 1998
J. Am. Chem. Soc., 1919, 41 (12), pp 2121–2130
Chem. Res. Toxicol., 2010, 23 (1), pp 240–250
[Edited on 22-2-2013 by kavu]Magpie - 19-2-2013 at 15:49
It should also be noted that the short-chain variants are not pungent nor irritant. With longer chains the final product has to be handled with utmost
care though!
Why do you think this is? I would have expected just the opposite.
What is the offensive characteristic of the longer chained variants?kavu - 20-2-2013 at 00:32
Activity is greatly dependent on the side chain length. Longer the side chain the more lipophilic the molecule. This lipophilicity is essential when
binding with TrpV1 receptor and leading to sensations of pain and heat. An article described capsaisin derivative activities with respect to side
chains. They found the activity to peak at around 8-9C, the exact length of capsaicin. The offensive characteristics are similar to those of capsaicin
itself: instant irritation on contact and a lasting sensation of burning.
[Edited on 20-2-2013 by kavu]Hexavalent - 24-2-2013 at 02:48
Very nice!
When you say "Vanillyl oxime (1.00 g, 6.00 mmol) was dissolved in 10 ml of acetic acid", I assume you mean glacial acetic acid?Nicodem - 24-2-2013 at 03:43
Acetic acid is glacial acetic acid. "Glacial" only means that it is anhydrous enough for it to have the literature value of its melting
point. For this reason, it is a purely obsolete term and you rarely see it used in the literature. However, for some reason there are numerous members
of this forum who like to use it and for this reason I can see where your confusion comes from.
Kavu, thank you very much for your contribution, but even though the procedure is literature based, I miss at least some minimal characterization
data. A bit of comments at least on the TLC purities or melting points where applicable would greatly improve the quality. Also, for better
readability and ease to those interested in the topic, it would help to numerate and cite references already in the text.
For longer chain amides, the boric acid catalyzed amidation would be more practical than bothering with activating reagents or going through the acid chlorides/anhydrides.
Interestingly, there are even simpler capsaicinoids than vanillyl amides of fatty acids. One such are the fatty acid morpholides (see DOI: 10.1021/ja01643a043).DJF90 - 24-2-2013 at 05:59
In the reduction of the oxime, you filter off the excess zinc but don't seem to afford any separation from the dissolved zinc (II). Adding ammonia
(gaseous? aqueous? methanolic? What concentration if as solution) to neutralize (final pH = 7?) could precipitate some of the zinc; I've fallen ill of
this (i.e. having zinc (II) in my product) myself in the reduction of a nitrobenzene to the phenylhydroxylamine.
I certainly second Nicodem's request for characterisation data. A melting point at minimum, though an accompanying TLC would be nice. Even an amatuer
(I prefer the term "independant researcher") can manage this much.kavu - 24-2-2013 at 06:33
Thanks Nicodem and DJF90. I was aware of the product characterization problem and just started measuring the MPs. Problem with zinc ppt in the product
is truly a stupid overlooked mistake. I did the precipitation with 10 vol-% aqueous ammonia and stopped at around pH 8 in hopes not to ppt too much of
the zinc. I'm now running a second batch of vanillin through the sequence and I'll check the product for excess zinc (which there will be...).
Reduction this way is cheap, but getting rid of the Zn presents some problems as the amine is fairly soluble in water making extraction sequences
rather wasteful.
[Edited on 24-2-2013 by kavu]DJF90 - 24-2-2013 at 07:50
Don't worry about the oversight, like I said I've fallen ill of this before myself. Additionally, this may also explain the low yield in the final
step, so I guess every cloud has a silver lining. Alternative methods for the reductive amination exist, though its nice to see the use of the oxime.
Personally for something like this (making a simple primary amine from a relatively non-volatile aldehyde) I'd look into a leuckart reaction.mr.crow - 4-3-2013 at 08:12
Thanks kavu for the excellent post
Are you interested in forming more long chain spicy compounds? You could easily use fatty acids from vegetable oils. Perhaps methyl esters (i.e. bio
diesel) could be used to form the amide. Or use Nicodem's suggestion.
I believe Unintentional Chaos was working on constructing the actual Capsaicin side chain from 6-bromohexanoic acid with a Witting reaction. You could
PM him.
